2,6-di,2,4,6-, 2,5,6-tri and 2,4,5,6-tetra-substituted pyrimidines, their pharmaceutically acceptable salts, pharmaceutical compositions containing same and their use in the treatment of neurological diseases

ABSTRACT

2-Substituted pyrrelo[2,3-d]pyrimidines are useful for the treatment of neurological diseases.

This invention relates to novel pyrimidines or their pharmaceuticallyacceptable salts, and novel therapeutic agents for neurological diseasesof the peripheral and central nervous systems of animals containing theabove compounds as active ingredients.

Japanese Patent Publication No. 23,394/1971 discloses thataminopyrimidines represented by the following formula ##STR1## wherein Arepresents an alkylene group having up to 16 carbon atoms, or a loweralkylene group substituted by an amino group or a C₂₋₅ acylamino group,M represents H, Na, K, NH₄, Mg, Ca or an organic basic ammonium salt,and n is a value equal to the atomic valency of M,

have interesting therapeutic activity, particularly as ananti-melanchoric agent and psychoanaleptic agent in the field ofpsychosis.

Japanese Patent Publication No. 22044/1976 discloses that dichloro-loweraliphatic carboxylic acid salts of 2-isopropylaminopyrimidine, such as2-isopropylaminopyrimidine dichloroacetate, are useful as a therapeuticagent of a neurological disease.

Japanese Laid-Open Patent Publication No. 100477/1977 (PatentPublication No. 28548/1984) discloses that 2-isopropylaminopyrimidinephosphate is useful as a therapeutic agent for a ,neurological disease.

Japanese Laid Open Patent Publication No. 157575/1979 discloses aprocess for producing 2-chloropyrimidine in a high yield. A workingexample in this patent publication describes the preparation of2-chloropyrimidine in a yield of 69 %.

Japanese Laid-Open Patent Publication No. 393/1980 discloses a processfor producing 2-isopropyl-aminopyrimidine in a high yield. A workingexample of this patent publication describes the preparation of2-isopropylaminopyrimidine in a yield of 60 %.

Japanese Laid-Open Patent Publication No. 122768/1980 discloses that ahydroxy derivative of 2-isopropylaminopyrimidine represented by thefollowing formula ##STR2## wherein A⁴, A⁵ and A⁶ each represent H or OH,and at least one of them represents OH, is useful in the field of nerveregeneration and for treatment of myodystrophy.

Japanese Laid-Open Patent Publication No. 145670/1980 discloses that2-isopropylaminohalogenopyrimidines represented by the following formula##STR3## wherein A₄, A₅ ' and A₆ ' each represent H or a halogen atom,and at least one of them is a halogen atom,

are useful for treatment of various neurological diseases andmyodystrophy.

Japanese Laid-Open Patent Publication No. 145,671/1980 discloses aprocess for producing a hydroxy derivative of2-isopropylaminopyrimidine.

Japanese Laid-Open Patent Publication No. 151,571/1980 discloses that2-isopropylamino-5-halo9enopyrimidines are interesting in the treatmentof neurological diseases.

Japanese Laid-Open Patent Publication No. 10177/1981 discloses a processfor producing 2-isopropylaminopyrimidine substantially in a quantitativeyield by aminolyzing 2-methylsulfonylpyrimidine with isopropylamine.

Japanese Laid-Open Patent Publication No. 26880/1981 discloses a processfor producing 2-isopropylaminopyrimidine which comprises reactingbis(isopropylguanidine) sulfate with 1,1,3,3-tetraethoxypropane.

Japanese Laid-Open Patent Publication No. 90,013/1981 describes atherapeutic agent for myodystropy, myopathy, muscle rigidity and/ordysfunction of neuro-musclar transmission comprising substitutedderivative of pyrimidine or its therapeutically acceptable salt or itsmetabolite as an active ingredient. However, it merely discloses varioussalts such as an orthophosphate, of 2-isopropylaminopyrimidine as anactive compound.

Japanese Laid-Open Patent Publication No. 65873/1986 discloses that2-piperazinopyrimidines of the following formula ##STR4## wherein R¹ isH or aralkyl, and Y is a divalent organic group defined in the claim ofthis patent publication,

are useful as a herbicide for paddies and upland farms.

The present inventors previously provided a novel therapeutic agent fortreatment of neurological diseases comprising a specific2-piperazinopyrimidine derivative or its pharmaceutically acceptablesalt (International Laid-Open No. W087/04928).

It is an object of this invention to provide novel pyrimidines and theirpharmaceutically acceptable salts.

Another object of this invention is to provide therapeutic agents forneurological diseases and spinal breakdown comprising the above novelcompounds.

Another object of this invention is to provide a novel therapeutic agentfor neurological diseases having the effect of regenerating andrepairing nerve cells.

Another object of this invention is to provide a novel therapeutic agentfor neurological diseases which can be applied to disorders ofperipheral nerves, cerebrospinal injury, etc.

Another object of this invention is to provide a novel therapeutic agentfor neurological diseases which can be applied to diseases of centralnerves which are different from psycosis and in which abnormality in theoperating system or the metabolic system of chemical transmitters isregarded as being primarily involved

Another object of this invention is to provide a novel therapeutic agentfor cerebral diseases which has the effect of improving and restoringlearning and memory.

Another object of this invention is to provide a novel therapeutic agentfor neurological diseases or cerebral diseases, which comprises acomprehensively excellent and useful compound having pharmacologicalactions suitable for treatment of neurological diseases or cerebraldiseases with little side effects such as liver trouble.

Further objects of this invention along with its advantages will becomeapparent from the following description.

According to this invention, there is first provided a pyrimidinerepresented by the following formula (1), or its pharmaceuticallyacceptable salt ##STR5## wherein R¹ represents a hydrogen atom or alower alkyl group; X represents a group of the formula ##STR6## a groupof the formula ##STR7## in which R² represents a hydrogen atom, a loweralkyl group, a phenyl group, a benzyl group or analpha-(p-chlorophenyl)benzyl group,

a group of the formula ##STR8## in which R³ corresponds to one or atleast two identical or different substituents replacing one or at leasttwo hydrogen atoms of identical or different methylene groups, andrepresents a lower alkyl group, a hydroxyl group, a phenyl groupoptionally substituted by nitro, a benzyl group, a benzoyloxy group, abenzoylamino group, a lower alkylamino group, a di-lower alkylaminogroup, the HO(C₆ H₅)₂ C-- group, a piperidino group, a hydroxy(loweralkyl) group, the C₆ H₅ SO₂ O-- group, a benzoyl group optionallysubstituted by halogen, a lower alkylsulfonylamide group or a loweralkoxycarbonyl group, and n is a number of 4, 5, 6 or 7,

a group of the formula ##STR9## in which R⁴ represent a hydrogen atom, alower alkyl group or a benzyl group, and R⁵ represents a lower alkylgroup, a lower acyl group, a 2-furoyl group, a benzyl group, a4-piperidyl group optionally substituted by benzoyl, a phenethyl group,the group ##STR10## or a benzoyl group optionally substituted by halogenor nitro, a group of the formula ##STR11## a group of the formula##STR12## a group of the formula ##STR13## or a group of the formula##STR14## Y represents a group of the formula

    --CH.sub.2 R.sup.9

wherein R⁹ represents a hydrogen atom, a lower alkyl group, a loweralkoxy group, a lower alkylthio group, or a di-lower alkylamino group,

a group of the formula ##STR15## wherein R⁶ represents a hydrogen atom,a lower alkyl group, a phenyl group, a benzyl group, a lower alkoxygroup or a 2-(N,N,-dimethylamino)ethyl group, and R⁷ represents a loweralkyl group, a lower acyl group, a cyclohexylcarbonyl group, a 2-furoylgroup, a lower alkoxycarbonyl group, a cinnamoyl group, a benzyl group,a benzylcarbonyl group, a tosyl group, a phenoxyacetyl group, a di-loweralkylcarbamoyl group, a 2-thienyl group, a group of the formula##STR16## a group of the formula ##STR17## a group of the formula##STR18## a group of the formula ##STR19## a group of the formula##STR20## a 4-lower alkylpiperazyl group, or a benzoyl group optionallysubstituted by halogen, nitro, lower alkyl, lower alkoxy, amino,benzoylamino or phenyl, provided that when R⁶ is a hydrogen atom, R⁷ isa benzoyl group,

a group of the formula ##STR21## wherein R⁸ corresponds to a substituentreplacing the hydrogen atom of the methylene group, and represents ahydrogen atom, a lower alkyl group, a phenyl group or a benzyl group,and m is a number of 4, 5, 6 or 7,

a group of the formula ##STR22## a group of the formula ##STR23## or agroup of the formula ##STR24## and Z represents a hydrogen atom, ahalogen atom, a lower alkyl group or a lower alkoxycarbonyl group;provided that Y represents --CH₂ R⁹ only when Z is a loweralkoxycarbonyl group; that R⁴ represents a hydrogen atom only when R⁵represents a lower alkyl group, a lower acyl group, a 2-furoyl group, abenzyl group, a phenethyl group or a benzoyl group optionallysubstituted by halogen or nitro, Y represents CH₂ R⁹ and Z represents alower alkoxy carbonyl group; that Y can be ##STR25## and R⁴ is a loweralkyl group.

In formula (1l), R¹ is a hydrogen atom or a lower alkyl group. The loweralkyl group may be linear or branched, and preferably has 1 to 4 carbonatoms. Examples include methyl, ethyl, n-propyl, isopropyl n-butyl,sec-butyl, isobutyl and t-butyl groups.

In formula (I), X represents a group of the formula ##STR26##

In the above formulae, R² represents a hydrogen atom, a lower alkylgroup, phenyl group, benzyl group or an alpha-(p-chlorophenyl)benzylgroup. Examples of the lower alkyl group may be the same as thoseexemplified for R¹.

R³ corresponds to a substituent replacing the hydrogen atom of themethylene group, and represents a lower alkyl group, a hydroxyl group, aphenyl group optionally substituted by nitro, a benzyl group, abenzoyloxy group, a benzoylamino group, a lower alkylamino group, adi-lower alkylamino group, the HOL(C₆ H₅)₂ C--group, a piperidino group,a hydroxy(lower alkyl) group, the C₆ H₅ SO₂ O-- group, a benzoyl groupoptionally substituted by halogen, a lower alkylsulfonylamide group, ora lower alkoxycarbonyl group. n is a number of 4, 5, 6 or 7. Examples ofthe lower alkyl groups may be the same as those exemplified above withregard to R¹.

R⁴ represents a hydrogen atom, a lower alkyl group or a benzyl group,and R⁵ represents a lower alkyl group, a lower acyl group, a 2-furoylgroup, a benzyl group, a 4-piperidyl group optionally substituted bybenzoyl, a phenethyl group or the group ##STR27## or a benzoyl groupoptionally substituted by halogen or nitro.

Examples of the lower alkyl groups for R⁴ and R⁵ may be the same asthose R⁵.

The alkyl moiety of the lower acyl group for R⁵ may be linear obranched.

Acyl groups having 2 to 6 carbon atoms are preferred, and examplesinclude acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl andhexanoyl groups.

In formula (I), Y represents a group of the formula ##STR28##

R⁹ represents a hydrogen atom, a lower alkyl group, a lower alkoxygroup, a lower alkylthio group, or a di-lower alkylamino group. R⁶represents a hydrogen atom, a lower alkyl group, a phenyl group, abenzyl group, a lower alkoxy group or a 2-(N,N-dimethylamino)ethylgroup. R⁷ represents a lower alkyl group, a lower acyl group, acyclohexylcarbonyl group, a 2-furoyl group, a lower alkoxycarbonylgroup, a cinnamoyl group, a benzyl group, a benzylcarbonyl group, atosyl group, a phenoxyacetyl group, a di-lower alkylcarbamoyl group, a2-thienyl group, a group of the formula ##STR29## a group of the formula##STR30## a group of the formula ##STR31## a group of the formula##STR32## a group of the formula ##STR33## a 4-lower alkylpiperazylgroup, or a benzoyl group which may be substituted by halogen, loweralkoxy, nitro, amino, benzoylamino or phenyl.

Examples of the lower alkyl groups for R⁹, R⁶ and R⁷ may be the same asthose exemplified with respect to R¹.

Examples of the lower acyl group for R⁷ may be the same as thoseexemplified above for R⁵.

Examples of the halogen and lower alkoxy group as substituent for thebenzoyl group R⁷ are fluorine, chlorine, bromine and iodine, and alkoxygroups having 1 to 4 carbon atoms such as methoxy, ethocy, propoxy,isopropoxy, butoxy, isobutoxy and sec-butoxy. When R⁶ is a hydrogenatom, R⁷ is a benzoyl group.

Furthermore, in formula (1), Z represents a hydrogen atom, a halogenatom, a lower alkoxycarbonyl group or a lower alkyl group.

Examples of the halogen atom are fluorine, chlorine, bromine and iodine.Examples of the lower alkyl group may be the same as those exemplifiedwith respect to R¹.

According to this invention, there is further provided a compoundrepresented by the following formula (2), or its pharmaceuticallyacceptable salt, ##STR34## wherein A₁ represents ═CH-- or --N═; A₂ is═CH═, --N═, or ##STR35## A₃ represents ═CH-- or --N═; R¹¹ represents alower alkyl group; R¹² represents a phenyl group optionally substitutedby halogen, lower alkyl or lower alkoxy, a 2-furyl group, or a 2-thienylgroup; provided that

when A₁ is --N═, A₂ is ##STR36## when A₁ and A₂ are ═CH--, A₃ is ═CH--,and when A₂ is --N═, A₁ and A₃ are ═CH--.

In formula (2), R¹¹ is a lower alkyl group. R¹² represents a phenylgroup optionally substituted by halogen, lower alkyl or lower alkoxy, a2-furyl group or a 2-thienyl group.

Examples of the lower alkyl groups for R¹¹ and R¹² may be the same asthose exemplified above with regard to R¹.

A₁ is ═CH-- or ═N--, and A₂ is ═CH--, --N═, or ##STR37## A₃ is ═CH-- or--N═. When A₁ is --N═, A₂ is ##STR38## When A₁ and A₂ are ═CH--, A₃ is═CH--. When A₂ is --N═, A₁ and A₂ are ═CH--.

According to still another aspect, there is also provided a novelcompound of the following formula (3) having the same pharmacologicalefficacy.

A pyrimidine of formula (3), or its pharmaceutically acceptable salt,##STR39## wherein A represents a group of the formula ##STR40## R²¹represents a group of the formula (a) ##STR41## wherein R²³ represents ahydrogen atom, a lower alkyl group, a lower alkoxy group or a phenylgroup and R²⁴ represents a hydrogen atom, a lower alkyl group, acyclohexyl group, a phenyl group, a 4-halogenophenyl group, a p-diphenylgroup, a 2l-pyridyl group or a 2-thiophenyl group, provided that R²³ andR²⁴ are not hydrogen atoms at the same time;

or a group of the formula (b) ##STR42## which is a 9-fluorenyl group ora triphenylmethyl group; R²² represents a lower alkyl group; and l is anumber of 0 or 1.

In formula (3), A represents a group of the formula ##STR43## R²¹represents a group of the following formula (a) ##STR44## or a group ofthe following formula (b) which is a 9-fluorenyl or triphenylmethylgroup.

R²³ in formula (a) is a hydrogen atom, a lower alkyl group, a loweralkoxy group or a phenyl group, and R²⁴ represents a hydrogen atom, alower alkyl group, a cyclohexyl group, a phenyl group, a4-halogenophenyl group, a p-diphenyl group, a 2-pyridyl group, or a2-thiophenyl group. R²³ and R²⁴ are not hydrogen atoms at the same time.

The lower alkyl groups for R²³ and R²⁴, independently from each other,may be linear or branched and preferably contain 1 to 4 carbon atoms.Examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl andisobutyl groups.

The lower alkoxy group for R²³ may be linear or branched, and thosehaving 1 to 4 carbon atoms are preferred. Examples include methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy andt-butoxy groups. Examples of the 4-halogenophenyl group for R²⁴ are4-fluorophenyl, 4-chlorophenyl or 4-bromophenyl.

In formula (3), R²² is a lower alkyl group examples of which may be sameas those given for R²³. is a number of 0 or 1.

Examples of formulae (1), (2) and (3) provided by this invention aregiven below. ##STR45##

The compounds of formulae (1), (2l) and (3) may be produced by knownmethods, particularly the methods described in Japanese Laid-Open PatentPublication Nos. 140568/1986 and 87627/1986, or by treating theintermediates obtained by these methods in accordance with known methods(for example, the elimination of the protecting group by reduction).Examples 1 to 9 given hereinafter describe the production of thesecompounds in detail.

For example, compounds of formula (I) in which Y is --NR⁶ R⁷ and R⁶ isother than hydrogen may be produced by the following reaction scheme 1.##STR46##

Compounds of general formula (1) in which X is --NR⁴ R⁵ may be producedby the following reaction scheme 2. ##STR47##

The starting compounds of formulae (II) and (III) in the reactionschemes 1 and 2 may be produced by the method described at J. Chem.Soc., 1965, pages 755-761, from ##STR48## as a starting material. Thereactions in the reaction schemes 1 and 2 are conveniently carried outat a temperature of 20° to 150° C. in a solvent such as toluene,dioxane, pyridine or water in the presence of, as required, a basiccompound. The basic compound may conveniently be, for example, anorganic base (such as triethylamine, pyridine and4-dimethylaminopyridine), and an inorganic base (such as sodiumcarbonate and potassium carbonate).

Compounds of general formula (1) in which Y is CH₂ R⁹, R⁹ is hydrogen ora lower alkyl group and Z is a lower alkoxycarbonyl group may beproduced in accordance with the following reaction scheme 3. ##STR49##

Specifically, by reacting compounds (IV) with (V) at a temperature of 20to 100° C. in a reaction medium such as water, methanol, ethanol, THFand DMF, compounds of formula (I) In which , and are obtained.

Compounds of general formula (I) in which Y is CH₂ R⁹, R⁹ is other thanhydrogen and lower alkyl group and Z is a lower alkoxycarbonyl group maybe produced in accordance with the reaction scheme 4. ##STR50##

Compound (VI) may be prepared in the same way as in Production MethodNo. 7) of Japanese Laid-Open Patent Publication No. 65873/1986 exceptthat X is used instead of benzylpiperazine. Compounds of formula (I) inwhich Y is CH₂ R⁹ and Z is COOR¹⁰ are obtained by reacting compound (VI)with R⁹ H in the presence of an organic base and as pyridine ortriethylamine, or an inorganic base such as potassium carbonate, sodiumcarbonate, potassium hydroxide, sodium hydroxide, potassium hydride orsodium hydride in the presence of an inert solvent such as toluene ortetrahydrofuran or in the absence of solvent.

The compounds of general formula (2) can be synthesized by the samemethods as in the synthesis of the compound of general formula (1).

The compounds of general formula (3) can be produced by the methodsshown in the following schemes 5 and 6. ##STR51##

The starting material (VII) may be produced by the method described inJ. A. C. S., 71, 2731 (1949). The reaction of the compound (VII) withN-formylpiperazine in a solvent such as acetonitrile ordimethylformamide or in the absence of solvent, optionally in thepresence of a basic compound, at a temperature of 20° to 150° C.,preferably 20° to 100° C, to form the compound (VIII). An inorganic basesuch as sodium carbonate or potassium carbonate, or an organic base suchas triethylamine or pyridine may be used as the basic compound. Compound(III) is then hydrolyzed in the presence of an acid or an alkali toyield compound (IV). The hydrolysis is carried out in a solvent such aswater, methanol or ethanol at a temperature of 0° to 150° C., preferably20° to 100° C. ##STR52##

Compounds of formula (3) are produced from compound (IV) or (X) inaccordance with scheme 5 by known methods, particularly the methodsdescribed in Japanese Laid-Open Patent Publications Nos. 140568/1986 and87627/1986 or by treating the intermediates obtained by these methods inaccordance with known methods (for example, the reductive elimination ofthe protective group). Examples 7 to 9 given below illustrate theproduction of the compounds of formula (3) in detail.

Investigations of the present inventors show that the compounds offormulae (1), (2) and (3) are useful as therapeutic agents for treatmentof neurological diseases.

The compounds of formulae (1), (2) and (3) are normally used in the formof a pharmaceutical composition, and are administered by various routes(e.g., oral, subcutaneous, intramuscular, intravenous, intrarhinal, skinpermeation and through the rectum).

The present invention also embraces a pharmaceutical preparationcomprising a compound of general formula (1), (2) or (3) or itspharmaceutically acceptable salt. The pharmaceutically acceptable saltincludes, for example, acid addition salts and quaternary ammonium (oramine) salts.

Examples of the pharmaceutically acceptable salts of the compounds (1),(2) and (3) include salts formed from acids capable of formingpharmaceutically acceptable non-toxic acid-addition salts containinganions, such as hydrochlorides, hydrobromides, sulfates, bisulfites,phosphates, acid phosphates, acetates, maleates, fumarates, succinates,lactates, tartrates, benzoates, citrates, gluconates, glucanates,methanesulfonates, p-toluenesulfonates and naphthalenesulfonates ortheir hydrates, and quaternary ammonium (or amine) salts or theirhydrates.

The composition of this invention may be formulated into tablets,capsules, powders, granules, troches, cachet wafer capsules, elixirs,emulsions, solutions, syrups, suspensions, aerosols, ointments, asepticinjectables, molded cataplasmas, tapes, soft and hard gelatin capsules,suppositories, and aseptic packed powders. Examples of thepharmaceutically acceptable carrier include lactose, glucose, sucrose,sorbitol, mannitol, corn starch, crystalline cellulose, gum arabic,calcium phosphate, alginates, calcium silicate, microcrystallinecellulose, polyvinyl pyrrolidone, tragacanth gum, gelatin, syrup, methylcellulose, carboxymethyl cellulose, methylhydroxybenzoic acid esters,propylhydroxybenzoic acid esters, talc, magnesium stearates, inertpolymers, water and mineral oils.

Both solid and liquid compositions may contain the aforesaid fillers,binders, lubricants, wetting agents, disintegrants, emulsifying agents,suspending agents, preservatives, sweetening agents and flavoringagents. The composition of this invention may be formulated such thatafter administration to a patient, the active compound is releasedrapidly, continuously or slowly.

In the case of oral administration, the compound of formula (1), (2) or(3) is mixed with a carrier or diluent and formed into tablets,capsules, etc. In the case of parenteral administration, the activeingredient is dissolved in a 10 % aqueous solution of glucose, isotonicsalt water, sterilized water or a like liquid, and enclosed in vials orampoules for intravenous instillation or injection or intramuscularinjection. Advantageously, a dissolution aid, a local anesthetic agent,a preservative and a buffer may also be included into the medium. Toincrease stability, it is possible to lyophilize the present compositionafter introduction into a vial or ampoule. Another example of parenteraladministration is the administration of the pharmaceutical compositionthrough the skin as an ointment or a cataplasm. In this case, a moldedcataplasm or a tape is advantageous.

The composition of this invention contains 0.1 to 2000 mg, moregenerally 0.5 to 1000 mg, of the active component for each unit dosageform.

The compound of formula (1), (2) or (3) is effective over a wide dosagerange. For example, the amount of the compound administered for one dayusually falls within the range of 0.03 mg/kg to 100 mg/kg. The amount ofthe compound to be actually administered is determined by a physiciandepending, for example, upon the type of the compound administered, andthe age, body weight, reaction condition, etc. of the patient and theadministration route.

The above dosage range, therefore, does not limit the scope of theinvention. The suitable number of administrations is 1 to 6, usually 1to 4, daily.

The compound of formula (1), (2) or (3) by itself is an effectivetherapeutic agent for disorders of the peripheral nervous system and thecentral nervous system. If required, it may be administered incombination with at least one other equally effective drug. Examples ofsuch an additional drug are gangliosides, mecobalamin and isaxonine.

The formulations of the compounds (1), (2) and (3) in accordance withthis invention and their biological activities will be illustrated indetail by a series of Examples B and Examples given below. It should beunderstood however that they do not limit the scope of the invention.Each of the following examples showing the composition of the inventionuses one of the compounds described hereinabove or one of otherpharmaceutically active compounds encompassed within general formula(1), (2) and (3).

REFERENTIAL EXAMPLE 1

4-Methylamino-2-(4-phenylpiperidino)pyrimidine (compound No. 1024):

To a solution of 17.0 g (0.11 mole) of 2,4-dichloropyrimidine in 150 mlof dichloromethane was added methylamine (0.25 mole, 20 ml of 40 %methanol solution) at such a rate that the temperature of the solutionwas maintained at 5 ° C. After the addition, the solution was stirred atroom temperature for 12 hours. The reaction mixture was concentratedunder reduced pressure, and extracted with dichloromethane. Thedichloromethane layer was dried over an anhydrous sodium sulfate, andconcentrated under reduced pressure to give 14.0 g (purity 80 %) of2-chloro-4-methylaminopyrimidine.

Two hundred milliliters of n-butanol was added to 3.0 g (0.02 mole) of2-chloro-4-methylaminopyrimidine and 8.4 g (0.05 mole) of4-phenylpiperidine, and the mixture was heated at 130 ° C. for 1 hour.The reaction mixture was concentrated under reduced pressure, andextracted with dichloromethane. The dichloromethane layer was dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography to give

4.0 g (yield 71 %) of the desired compound as an oil.

¹ H-NMR spectrum (deuterochloroform, δppm): 1.4-2.0(5H, m), 2.93(3H, d,J=5.2Hz), 2.6-3.1(2H, m), 4.60(1H, m), 4.92(2H, br. d, J=12.6Hz),5.67(1H, d, J=7.2Hz), 7.28(5H, s), 7.93(1H, d, J=7.2 Hz).

In a similar manner, the following compounds were produced. ##STR53##

The properties of the compounds (intermediate) are shown in Table 1below.

                  TABLE 1                                                         ______________________________________                                        Com-          Melting                                                         pound Yield   point    .sup.1 H-NMR spectrum                                  No.   (%)     (°C.)                                                                           (CDCl.sub.3 solution, δ ppm)                     ______________________________________                                        1000  51      Oil      2.90(3H, d, J = 5.2Hz), 3.13(6H, s),                                          4.66(1H, m), 5.63(1H, d, J = 5.2Hz),                                          7.88(1H, d, J = 5.2Hz)                                 1004  29      Oil      0.92(6H, m), 1.0-1.8(8H, m),                                                  2.88(3H, d, J = 5.2Hz), 3.51(4H, m),                                          4.55(1H, m), 5.56(1H, d, J = 5.2 Hz),                                         7.84(1H, d, J = 5.2Hz)                                 1008  68      Oil      1.92(4H, m), 2.88(3H, d, J = 5.2Hz),                                          3.52(4H, m), 4.76(1H, m),                                                     5.63(1H, d, J = 5.2Hz),                                                       7.88(1H, d, J = 5.2Hz)                                 1012  95      Oil      1.62(6H, br. s),                                                              2.92(3H, d, J = 5.4Hz),                                                       3.72(4H, br. s), 4.60(1H, m),                                                 5.64(1H, d, J = 6.0Hz),                                                       7.90(1H, d, J = 6.0Hz)                                 1016  72      Oil      0.95(3H, d, J = 5.2Hz),                                                       0.9-1.8(5H, m), 2.6-3.0(2H, m),                                               2.90(3H, d, J = 5.2Hz),                                                       4.69(2H, br. d, J = 12.6Hz),                                                  4.70(1H, m), 5.64(1H, d, J = 5.2Hz),                                          7.89(1H, d, J = 5.2Hz)                                 1020  62      Oil      0.9(9H, s), 1.0-1.9(5H, m),                                                   2.5-3.0(2H, m),                                                               2.90(3H, d, J = 5.2Hz), 4.6(1H, m),                                           4.80(2H, br. d, J = 12.6Hz),                                                  5.64(1H, d, J = 5.2Hz),                                                       7.9(1H, d, J = 5.2Hz)                                  1028  63      Oil      1.0-2.0(5H, m),                                                               2.54(2H, d, J = 5.2Hz),                                                       2.4-3.0(2H, m),                                                               2.87(3H, d, J = 5.2Hz), 4.65(2H, m),                                          4.72(2H, br. d, J = 12.6Hz),                                                  5.62(1H, d, J = 5.2Hz),                                                       7.0-7.4(5H, m),                                                               7.88(1H, d, J = 5.2Hz)                                 1032  66      96-98    1.7-2.2(2H, m), 2.8(2H, t, J = 7.2Hz)                                         2.89(3H, d, J = 5.2Hz),                                                       4.02(2H, t, J = 7.2Hz), 4.70(1H, m),                                          5.82(1H, d, J = 5.2Hz),                                                       6.8-7.3(3H, m),                                                               7.82(1H, d, J = 7.2Hz),                                                       7.99(1H, d, J = 5.2Hz)                                 1036  77      Oil      2.92(5H, m), 4.02(2H, t, J = 5.2Hz),                                          4.7(1H, m), 4.89(2H, s),                                                      5.67(1H, d, J = 7.2Hz), 7.18(4H, m),                                          7.94(1H, d, J = 7.2Hz)                                 1040  60      Oil      2.89(3H, d, J = 5.2Hz), 3.73(8H, s),                                          4.70(1H, m), 5.69(1H, d, J = 5.2Hz),                                          7.88(1H, d, J = 5.2Hz)                                 1048  56      Oil      2.32(3H, s), 2.43(4H, m),                                                     2.88(3H, d, J = 5.2Hz), 3.78(4H, m),                                          4.72(1H, m), 5.65(1H, d, J = 5.2Hz),                                          7.86(1H, d, J = 5.2Hz)                                 1052  56      120-122  2.91(3H, d, J = 4Hz), 3.24(4H, m),                                            3.95(4H, m), 4.60(1H, m),                                                     5.70(1H, d, J = 5.4Hz),                                                       6.8-7.4(5H, m),                                                               7.92(1H, d, J = 5.4Hz)                                 1056  68      Oil      2.48(4H, m), 2.87(3H, d, J = 5.2Hz),                                          3.53(2H, s), 3.77(4H, m),                                                     4.60(1H, m), 5.64(1H, d, J = 5.2Hz),                                          7.32(5H, m), 7.87(1H, d, J = 5.2Hz)                    1060  80      Oil      2.42(4H, m), 2.85(3H, d, J = 5.6Hz),                                          3.76(4H, m), 4.24(1H, s),                                                     4.56(1H, m), 5.65(1H, d, J = 5.6Hz),                                          7.0-7.5(9H, m),                                                               7.88(1H, d, J = 5.6Hz)                                 1064  61      Oil      1.4-2.2(4H, m), 2.5-3.1(3H, m),                                               4.62(2H, br. s),                                                              4.88(2H, br. d, J = 12.6Hz),                                                  5.72(1H, d, J = 5.2Hz), 7.25(5H, m),                                          7.94(1H, d, J = 5.2Hz)                                 1068  58      Oil      1.24(3H, t, J = 7.2Hz),                                                       1.4-2.0(4H, m), 2.5-3.1(3H, m),                                               3.1-3.5(2H, m), 4.58(1H, m),                                                  4.90(2H, br. d, J = 12.6Hz),                                                  5.65(1H, d, J = 5.2Hz),                                                       7.0-7.5(5H, m),                                                               7.92(1H, d, J = 5.2Hz)                                 1072  75      Oil      0.97(3H, t, J = 7.2Hz),                                                       1.4-2.1(6H, m), 2.5-3.1(3H, m),                                               3.24(2H, q, J = 7.2Hz),                                                       4.68(1H, br. s),                                                              4.88(2H, br. d, J = 12.6Hz),                                                  5.65(1H, d, J = 5.2Hz), 7.27(5H, m),                                          7.90(1H, d, J = 5.2Hz)                                 1076  57      Oil      1.4-2.0(4H, m), 2.5-3.1(3H, m),                                               4.52(2H, d, J = 5.2Hz),                                                       4.90(2H, br. d, J = 12.6Hz),                                                  4.91(1H, m), 5.68(1H, d, J = 5.2Hz),                                          7.0-7.5(10H, m),                                                              7.92(1H, d, J = 5.2Hz)                                 1080  36      Oil      1.4-2.0(4H, m), 2.27)6H, s),                                                  2.50(2H, m), 2.5-3.2(3H, m),                                                  3.36(2H, m), 3.46(2H, s),                                                     4.90(2H, br. d, J = 12.6Hz),                                                  5.24(1H, m), 5.67(1H, d, J = 5.2Hz),                                          7.27(5H, m), 7.88(1H, d, J = 5.2Hz)                    1084  50      91-93    1.60(6H, br. s), 2.23(3H, s),                                                 2.88(3H, d, J = 5.2Hz),                                                       3.75(4H, br. s), 4.50(1H, m),                                                 5.54(1H, s)                                            1088  57      Oil      1.5-2.0(4H, m), 2.23(3H, s),                                                  2.6-3.0(3H, m),                                                               2.90(3H, d, J = 5.2Hz), 4.51(1H, m),                                          4.96(2H, br. d, J = 12.6Hz),                                                  5.57(1H, s), 7.28(5H, s)                               1092  21      Oil      1.60(6H, br. s), 1.88(3H, s),                                                 3.0(3H, d, J = 5.2Hz),                                                        3.75(4H, br. s), 4.2(1H, br. s),                                              7.65(1H, s)                                            1096  75      Oil      1.4-2.0(4H, m), 1.92(3H, s),                                                  2.5-3.1(3H, m),                                                               3.02(3H, d, J = 5.2Hz), 4.40(1H, m),                                          4.90(2H, br. d, J = 12.6Hz),                                                  7.28(5H, m), 7.68(1H, s)                               1100  81      Oil      1.8-2.1(5H, m),                                                               2.79(2H, t, J = 7.2Hz),                                                       2.99(3H, d, J = 5.2Hz),                                                       4.03(2H, t, J = 7.2Hz), 4.42(1H, m),                                          6.8-7.2(3H, m), 7.7-8.0(2H, m)                         1104  48      121-124  1.4-2.1(4H, m), 2.5-3.1(3H, m),                                               3.02(3H, d, J = 4.0Hz), 4.85(1H, m),                                          4.88(2H, br. d, J = 12.6Hz),                                                  7.28(5H, m), 7.75(1H, d, J = 4.0Hz)                    1112  24      117-118  0.96(3H, d, J = 5.2Hz),                                                       0.9-1.8(5H, m), 2.6-3.0(2H, m),                                               2.96(3H, d, J = 5.2Hz),                                                       4.32(2H, br. d, J = 12.6Hz),                                                  4.80(1H, m), 5.88(1H, d, J = 5.2Hz),                                          7.87(1H, d, J = 5.2Hz)                                 1116  16      179-180  0.89(9H, s), 1.0-1.9(5H, m),                                                  2.5-3.0(2H, m),                                                               2.95(3H, d, J = 5.2Hz),                                                       4.45(2H, br. d, J = 12.6Hz),                                                  4.75(1H, m), 5.89(1H, d, J = 5.2Hz),                                          7.88(1H, d, J = 5.2Hz)                                 1120  18      148-154  1.4-2.1(5H, m),                                                               2.97(3H, d, J = 5.2Hz),                                                       2.6-3.1(2H, m),                                                               4.53(2H, br. d, J = 12.6Hz),                                                  5.95(1H, d, J = 7.2Hz), 7.28(5H, s),                                          7.88(1H, d, J = 7.2Hz)                                 1124  20      175-176  1.8-2.1(2H, m),                                                               2.76(2H, t, J = 7.1Hz),                                                       2.99(3H, d, J = 5.2Hz),                                                       3.96(2H, t, J = 7.2Hz), 4.9(1H, m),                                           6.32(1H, d, J = 5.2Hz),                                                       6.9-7.5(4H, m),                                                               7.88(1H, d, J = 5.2Hz)                                 1128  19      123-126  2.90(5H, m), 3.83(2H, t, J = 5.2Hz),                                          4.72(2H, s), 4.90(1H, m),                                                     5.92(1H, d, J = 7.2Hz), 7.19(4H, s),                                          7.92(1H, d, J = 7.2Hz)                                 1132  17      --       2.47(4H, m), 2.92(3H, d, J = 5.2Hz),                                          3.52(2H, s), 3.59(4H, m),                                                     4.75(1H, m), 5.84(1H, d, J = 5.2Hz),                                          7.32(5H, m), 7.85(1H, d, J = 5.2Hz)                    1136  17      158-160  1.24(3H, t, J = 7.2Hz),                                                       1.5-2.1(4H, m), 2.5-3.2(3H, m),                                               3.2-3.6(2H, m),                                                               4.52(2H, br. d, J = 12.6Hz),                                                  4.70(1H, m), 5.92(1H, d, J = 5.2Hz),                                          7.0-7.5(5H, m),                                                               7.89(1H, d, J = 5.2Hz)                                 1140  18      134-136  0.98(3H, t, J = 7.2Hz),                                                       1.4-2.1(6H, m), 2.6-3.1(3H, m),                                               3.35(2H, q, J = 7.2Hz),                                                       4.53(2H, br. d, J = 12.6Hz),                                                  4.80(1H, br. s),                                                              5.93(1H, d, J = 5.2Hz), 7.29(5H, m),                                          7.90(1H, d, J = 5.2Hz)                                 1144  13      158-160  1.2(3H, s), 1.27(3H, s),                                                      1.4-2.0(4H, m), 2.2-3.1(3H, m),                                               3.9-4.3(1H, m),                                                               4.52(2H, br. d, J = 12.6Hz),                                                  4.65(1H, m), 5.9(1H, d, J = 5.2Hz),                                           7.0-7.5(5H, m),                                                               7.89(1H, d, J = 5.2Hz)                                 1148  21      148-149  1.3-2.05(4H, m), 2.5-3.1(3H, m),                                              4.50(2H, br. d, J = 12.6Hz),                                                  4.60(2H, br. d, J = 5.2Hz),                                                   5.35(1H, m), 5.95(1H, d, J = 5.2Hz),                                          7.0-7.5(10H, m),                                                              7.88(1H, d, J = 5.2Hz)                                 1152  31      84-85    1.65(6H, br. s), 2.22(3H, s),                                                 2.95(3H, d, J = 5.2Hz),                                                       3.57(5H, br. s), 4.75(1H, m),                                                 5.77(1H, s)                                            1156  10      198-199  1.5-2.0(4H, m), 2.23(3H, s),                                                  2.6-3.1(3H, m),                                                               2.96(3H, d, J = 5.2Hz),                                                       4.4-4.8(3H, m), 5.83(1H, s),                                                  7.26(5H, m)                                            1160  83      162-165  2.03(3H, s), 3.12(3H, d, J = 5.2Hz),                                          4.90(1H, m), 7.2-7.5(3H, m),                                                  7.85(3H, m), 8.12(1H, s),                                                     8.6(1H, s)                                             ______________________________________                                    

REFERENTIAL EXAMPLE 2 4-Methylamino-2-(4-phenylpiperidino)pyrimidinemaleate (compound No. 1026)

A solution of 0.43 g (3.73 mmoles) of maleic acid in 10 ml of methanolwas added to a solution of 1.0 g (3.73 mmoles) of4-methylamino-2-(4-phenylpiperidino)pyrimidine in 10 ml of methanol, andthe mixture was stirred at room temperature for 1 hour. The mixedsolution was concentrated under reduced pressure and washed with etherto give 1.25 g (yield 87 %) of the desired product.

Melting point: 163°-166 ° C.

¹ H-NMR spectrum (CDCl₃ solution, δppm): 1.6-2.2(4H, m), 2.6-3.3(5H, m),3.04(3H, d, J=5.2Hz), 4.74(1H, br. d, J=12.6Hz), 6.30(1H, d, J=7.2Hz),7.30(5H, m), 7.71(1H, d, J=7.2Hz), 8.40(1H, m).

Similarly, the following compounds were produced.

(1014): maleate of (1012)

(1026): maleate of (1024)

(1034): maleate of (1032)

(1038): maleate of (1036)

(1086): maleate of (1084)

(1090): maleate of (1088)

(1094): maleate of (1092)

(1098): maleate of (1096)

(1102): maleate of (1100)

(1110): maleate of (1108)

(1122): maleate of (1120)

(1130) maleate of (1128)

(1158): maleate of (1156)

(1162): maleate of (1160)

The data of these compounds are given in Table 2 below.

                  TABLE 2                                                         ______________________________________                                        Com-          Melting                                                         pound Yield   point    .sup.1 H-NMR spectrum                                  No.   (%)     (°C.)                                                                           (CDCl.sub.3 solution, δ ppm)                     ______________________________________                                        1014  89      164-165  1.70(6H, br. s),                                                              3.02(3H, d, J = 3.8Hz),                                                       3.76(4H, br. s), 6.35(2H, s),                                                 7.65(1H, m), 8.32(1H, m),                                                     12.50(1H, m)                                           1034  94      42-46    1.9-2.3(2H, m),                                                               2.79(2H, t, J = 7.2Hz),                                                       3.01(3H, d, J = 5.2Hz),                                                       4.0(2H, t, J = 7.2Hz), 6.22(2H, s),                                           6.46(1H, d, J = 5.2Hz), 7.20(3H, m),                                          7.50(1H, m), 7.76(1H, d, J = 5.2Hz),                                          8.80(1H, m)                                            1038  77      149-151  2.9-3.2(5H, m),                                                               4.0(2H, t, J = 7.2Hz), 4.92(2H, s),                                           6.32(1H, d, J = 7.2Hz), 6.36(2H, s),                                          7.25(4H, s), 7.75(1H, d, J = 7.2Hz),                                          8.40(1H, m)                                            1086  99      155-157  1.68(6H, br. s), 2.28(3H, s),                                                 3.0(3H, d, J = 5.2Hz),                                                        3.80(4H, br. s), 6.0(1H, s),                                                  6.33(2H, s), 8.15(1H, m),                                                     11.7(1H, m)                                            1090  91      151-154  1.5-2.2(4H, m), 2.29(3H, s),                                                  2.6-3.3(6H, m),                                                               4.81(2H, br. d, J = 12.6Hz),                                                  6.02(1H, s), 6.32(2H, s),                                                     7.28(5H, br. s), 8.15(1H, m),                                                 12.2(1H, m)                                            1094  91      150-152  1.70(6H, br. s), 2.04(3H, s),                                                 3.08(3H, d, J = 5.2Hz),                                                       3.76(4H, br. s), 6.33(2H, s),                                                 7.15(1H, m), 7.59(1H, s)                               1098  92      163-165  1.6-2.2(4H, m), 2.03(3H, s),                                                  2.6-3.3(3H, m),                                                               3.09(3H, d, J = 5.2Hz),                                                       4.71(2H, br. d, J = 12.6Hz),                                                  6.33(2H, s), 7.0-7.4(5H, m),                                                  7.60(1H, s)                                            1102  81      145-150  1.8-2.3(5H, m),                                                               2.80(2H, t, J = 5.2Hz),                                                       3.08(3H, d, J = 5.2Hz),                                                       4.0(2H, t, J = 5.2Hz),                                                        6.25(2H, s), 7.1-7.6(4H, m),                                                  7.70(1H, s)                                            1110  91      187-188  1.74(6H, br. s), 2.32(3H, s),                                                 2.96(3H, d, J = 5.2Hz),                                                       3.5(2H, br. s), 3.95(2H, br, s),                                              5.83(1H, s), 6.33(2H, s),                                                     9.10(1H, m), 13.8(1H, m)                               1122  92      155-158  1.6-2.2(4H, m), 3.0(3H, d, J = 5.2Hz)                                         2.7-3.5(3H, m),                                                               4.10(1H, br. d, J = 12.6Hz),                                                  5.25(1H, br. d, J = 12.6Hz),                                                  6.12(1H, d, J = 7.2Hz), 6.33(2H, s),                                          7.30(5H, m), 7.50(1H, d, J = 7.2Hz),                                          9.0(1H, br. s)                                         1130  87      158-159  2.9-3.2(5H, d, J = 5.2Hz),                                                    3.79(1H, t, J = 5.2Hz),                                                       4.16(1H, t, J = 5.2Hz), 4.70(1H, s),                                          5.20(1H, s),                                                                  6.15(1H, br. d, J = 7.2Hz),                                                   6.30(2H, s), 7.27(4H, s),                                                     7.52(1H, d, J = 7.2Hz), 9.1(1H, m)                     1158  95      173-175  1.6-2.2(4H, m), 2.32(3H, s),                                                  2.6-3.5(6H, m), 4.1(1H, m),                                                   5.2(1H, m), 5.88(1H, s),                                                      6.34(2H, s), 7.30(5H, br. s),                                                 9.20(1H, m), 13.9(1H, m)                               1162  74      179-180  2.11(3H, s), 3.11(3H, d, J = 7.2Hz),                                          6.32(2H, s), 6.50(1H, m),                                                     7.2-8.0(6H, m), 8.20(1H, s),                                                  8.84(1H, s)                                            ______________________________________                                    

REFERENTIAL EXAMPLE 3 1-Diphenylmethylpiperazine

11.2 g (98 mmoles) of 1-formylpiperazine was added to 10 g (49 mmoles)of chlorodiphenylmethane, and the solution was stirred at roomtemperature for 48 hours, and the mixture was extracted with water andmethylene chloride. The organic layer was dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography, and 8.9 g(31.9 mmoles) of the resulting formyl compound was dissolved in 100 mlof ethanol, and 6.5 g (64 mmoles) of conc. hydrochloric acid was added,and the solution was refluxed for 1 hour. Then, the solvent wasevaporated under reduced pressure, and the residue was extracted with K₂CO₃ /water/CH₂ C₂. The organic layer was dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure to give6.8 9 (yield 55 %) of the desired product.

Melting point: 93°-95 ° C.

¹ H-NMR spectrum (CDCl₃ solution, δppm): 2.33(4H, m), 2.87(4H, m),4.19(1H, s), 7.1-7.5 (10H, m).

EXAMPLE 1 4-(N-methylbenzamino)-2-(4-phenylpiperidino)pyrimidine(compound No. 164.)

A solution of 5.2 g (0.037 mole) of benzoyl chloride in 50 ml oftetrahydrofuran was added at room temperature over 30 minutes to asolution of 9.0 g (0.034 mole) of4-methylamino-2-(4-phenylpiperidino)pyrimidine in 90 ml oftetrahydrofuran and 5 ml of triethylamine. Two hours after the end ofthe addition, 1 ml of pyridine was added. The mixture was then stirredfor 2 days. The reaction mixture was extracted with dichloromethane. Thedicloromethane layer was dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to give 8.8 g (yield 70 %) of the desiredcompound as an oil.

¹ H-NMR spectrum (deuterochloroform, δppm): 1.4-2.0(4H, m), 2.5-3.0(3H,m), 3.55(3H, s), 4.62(2H, br. d, J=12.6Hz), 6.14(1H, d, J=7.2Hz),7.1-7.6(10H, m), 8.06(1H, d, J=7.2Hz).

Data of compounds produced in the same way as above are shown in Table 3below.

                  TABLE 3                                                         ______________________________________                                        Com-          Melting                                                         pound Yield   point     .sup.1 H-NMR spectrum                                 No.   (%)     (°C.)                                                                            (CDCl.sub.3 solution, δ ppm)                    ______________________________________                                         100  48      Oil       3.0(6H, s), 3.52(3H, s),                                                      6.04(1H, d, J=5.2Hz),                                                         7.1-7.5(5H, m),                                                               7.98(1H, d, J=5.2Hz)                                   108  30      Oil       0.93(6H, m), 1.0-1.7(8H, m),                                                  3.2-3.65(4H, m), 3.50(3H, s),                                                 6.04(1H, d, J=5.2Hz),                                                         7.1-7.6(5H, m),                                                               7.96(1H, d, J=5.2Hz)                                   116  41      Oil       1.92(4H, m), 3.38(4H, m),                                                     3.53(3H, m), 6.0(1H, d, J=5.2Hz),                                             7.2-7.5(5H, m),                                                               7.96(1H, d, J=5.2Hz)                                   124  63      Oil       1.67(6H, br. s), 2.35(3H, s),                                                 3.38(3H, s), 3.78(4H, m),                                                     6.52(1H, d, J=6.0Hz),                                                         8.25(1H, d, J=6.0Hz)                                   132  55      Oil       1.55(6H, m), 3.53(3H, s),                                                     3.56(4H, m),                                                                  6.08(1H, d, J=5.2Hz),                                                         7.40(5H, m), 8.04(1H, d, J=5.2Hz)                      140  71      Oil       1.92(3H, d, J=5.2Hz),                                                         0.8- 1.8(5H, m), 2.7(2H, m),                                                  3.52(3H, s),                                                                  4.44(2H, br. d, J=12.6Hz),                                                    6.08(1H, d, J=5.2Hz),                                                         7.40(5H, m), 8.04(1H, d, J=5.2Hz)                      148  34      Oil       0.88(9H, s), 1.0-1.8(5H, m),                                                  2.63(2H, m), 3.53(3H, s),                                                     4.55(2H, br. d, J=12.6Hz),                                                    6.08(1H, d, J=5.2Hz),                                                         7.2-7.7(5H, m),                                                               8.05(1H, d, J=5.2Hz)                                   156  71      Oil       1.4-2.0(4H, m), 2.5-3.2(3H, m),                                               4.91(2H, br. d, J=12.6Hz),                                                    7.0-7.7(7H, m), 7.90(2H, m),                                                  8.32(2H, m)                                            172  20      Oil       1.33(3H, t, J=7.2Hz),                                                         1.4-2.0(4H, m),                                                               2.5-3.0(3H, m),                                                               4.13(2H, q, J=7.2Hz),                                                         4.64(2H, br. d, J=12.6Hz),                                                    6.01(1H, d, J=5.2Hz),                                                         7.0-7.7(10H, m,),                                                             8.04(1H, d, J=5.2Hz)                                   180  37      Oil       0.98(3H, t, J=7.2Hz),                                                         1.3-2.0(6H, m), 2.5-3.01(3H, m),                                              4.03(2H, t, J=7.2Hz),                                                         4.63(2H, br. d, J=12.6Hz),                                                    6.0(1H, d, J=5.2Hz),                                                          7.1-7.6(10H, m),                                                              8.04(1H, d, J=5.2Hz)                                   188  59      Oil       1.2-2.0(4H, m), 2.5-3.0(3H, m),                                               4.60(2H, br. d, J=12.6Hz),                                                    5.28(2H, s),                                                                  5.95(1H, d, J=5.2Hz),                                                         7.0-7.70(15H, m),                                                             7.96(1H, d, J=5.2Hz)                                   196  60      Oil       1.2-2.0(4H, m), 2.56(6H, s),                                                  2.5-3.10(5H, m),                                                              4.36(2H, t, J=8Hz),                                                           4.67(2H, br. d, J=12.6Hz),                                                    6.0(1H, d, J=5.6Hz),                                                          7.0-7.6(10H, m),                                                              8.0(1H, d, J=5.6Hz)                                    204  28      Oil       1.5-2.1(4H, m), 2.35(3H, s),                                                  2.6-3.2(3H, m), 3.40(3H, s),                                                  4.90(2H, br. d, J=12.6Hz),                                                    6.60(1H, d, J=12.6Hz),                                                        7.28(5H, m), 8.28(1H, d, J=7.2Hz)                      212  34      88-94     1.16(6H, d, J=7.2Hz),                                                         1.4-2.1(4H, m),                                                               2.6-3.3(4H, m), 3.36(3H, s),                                                  4.88(2H, br. d, J=12.6Hz),                                                    6.51(1H, d, J=5.2Hz),                                                         7.24(5H, m), 8.24(1H, d, J=5.2Hz)                      220  45      Oil       1.25(9H, s), 1.5-2.0(4H, m),                                                  2.6-3.2(3H, m), 3.29(3H, s),                                                  4.91(2H, br. d, J=12.6Hz),                                                    6.50(1H, d, J=5.2Hz),                                                         7.26(5H, m), 8.26(1H, d, J=5.2Hz)                      228  35      Oil       1.0-2.1(14H, m), 2.6-3.2(4H, m),                                              3.36(3H, s),                                                                  4.90(2H, br. d, J=12.6Hz),                                                    6.50(1H, d, J=5.2Hz),                                                         7.25(5H, m), 8.25(1H, d, J=5.2Hz)                      236  66      101-104   1.3-2.0(4H, m), 2.5-3.0(3H, m),                                               3.52(3H, s),                                                                  4.60(2H, br. d, J=12.6Hz),                                                    6.11(1H, d, J=5.2Hz),                                                         7.1-7.5(9H, m),                                                               8.10(1H, d, J=5.2Hz)                                   244  33      Oil       1.2-2.0(4H, m), 2.5-3.0(3H, m),                                               3.51(3H, s),                                                                  4.56(2H, br. d, J=12.6Hz),                                                    6.15(1H, d, J=5.2Hz),                                                         7.0-7.5(9H, m),                                                               8.10(1H, d, J=5.2Hz)                                   260  41      Oil       1.2-1.9(4H, m), 2.4-2.9(3H, m),                                               3.56(3H, s),                                                                  4.49(2H, br. d, J=12.6Hz),                                                    6.16(1H, d, J=3.6Hz),                                                         7.0-7.5(5H, m),                                                               7.6(2H, d, J=9.5Hz),                                                          8.16(1H, d, J=3.6Hz),                                                         8.20(2H, d, J=9.5Hz)                                   268  27      Oil       1.4-2.0(4H, m), 2.5-3.0(3H, m),                                               3.55(3H, s), 3.79(3H, s),                                                     4.72(2H, br. d, J=12.6Hz),                                                    6.07(1H, d, J=5.2Hz),                                                         6.81(2H, m), 7.1-7.6(7H, m),                                                  8.05(1H, d, J=5.2Hz)                                   276  57      Oil       1.4-2.0(4H, m), 2.5-3.1(3H, m),                                               3.53(3H, s), 3.79(6H, s),                                                     3.84(3H, s),                                                                  4.70(2H, br. d, J=12.6Hz),                                                    6.13(1H, d, J=5.2Hz),                                                         6.70(2H, s), 7.22(5H, m),                                                     8.05(1H, d, J=5.2Hz)                                   292  44      Oil       1.5-2.0(4H, m), 2.6-3.1(3H, m),                                               3.55(3H, s),                                                                  4.77(2H, br. d, J=12.6Hz),                                                    6.24(1H, d, J=5.2Hz),                                                         6.44(1H, dd, J=3.2, 2.0Hz),                                                   7.0(1H, dd, J=3.0, 1.0Hz),                                                    7.1-7.5(6H, m),                                                               8.16(1H, d, J=5.2Hz)                                   300  84      Oil       0.5-2.0(5H, m), 2.2-2.6(4H, m),                                               3.59(3H, s),                                                                  3.76(2H, br. d, J=12.6Hz),                                                    6.06(1H, d, J=5.2Hz),                                                         7.0-7.6(10H, m),                                                              8.0(1H, d, J=5.2Hz)                                    308  35      Oil       2.37(3H, s),                                                                  2.95(2H, t, J=5.2Hz),                                                         3.41(3H, s),                                                                  4.05(2H, t, J=5.2Hz),                                                         4.92(2H, s),                                                                  6.64(1H, d, J=5.2Hz),                                                         7.22(4H, s), 8.32(1H, d, J=5.2Hz)                      316  96      Oil       1.85-2.20(2H, m), 2.33(3H, s),                                                2.80(2H, t, J=5.2Hz), 3.40(3H, s),                                            4.04(2H, t, J=5.2Hz),                                                         6.93(1H, d, J=5.2Hz),                                                         6.95-7.30(3H, m),                                                             7.72(1H, dd, J=7.2, 2.0Hz),                                                   8.34(1H, d, J=5.2Hz)                                   324  79      Oil       1.6-2.1(2H, m),                                                               2.76(2H, t, J=5.2Hz), 3.52(3H, s),                                            3.80(2H, t, J=5.2Hz),                                                         6.39(1H, d, J=5.2Hz),                                                         6.9-7.7(9H, m),                                                               8.15(1H, d, J=5.2Hz)                                   332  42      Oil       3.52(3H, s), 3.59(8H, m),                                                     6.18(1H, d, J=5.2Hz), 7.36(5H, m),                                            8.04(1H, d, J=5.2Hz)                                   340  33      Oil       2.18(1H, s), 2.79(4H, m),                                                     3.51(3H, s), 3.56(4H, m),                                                     6.12(1H, d, J=5.2Hz), 7.35(5H, m),                                            8.02(1H, d, J=5.2Hz)                                   348  19      Oil       2.31(3H, s), 2.36(4H, m),                                                     3.52(3H, s), 3.60(4H, m),                                                     6.12(1H, d, J=5.2Hz),                                                         7.1-7.5(5H, m),                                                               8.01(1H, d, J=5.2Hz)                                   356  72      Oil       3.10(4H, m), 3.56(3H, s),                                                     3.76(4H, m), 6.20(1H, d, J=5.4Hz),                                            6.90(3H, m), 7.1-7.6(7H, m),                                                  8.09(1H, d, J=5.4Hz)                                   364  52      Oil       2.36(4H, m), 3.4-3.8(9H, m),                                                  6.11(1H, d, J=5.2Hz),                                                         7.1-7.6(10H, m),                                                              8.01(1H, d, J=5.2Hz)                                   372  50      58-62     2.32(4H, m), 3.49(3H, s),                                                     3.62(4H, m), 4.23(1H, s),                                                     6.13(1H, d, J=5.2Hz),                                                         7.0-7.6(14H, m),                                                              8.02(1H, d, J=5.2Hz)                                   380  63      Oil       1.65(6H, br. s), 2.29(3H, s),                                                 2.35(3H, s), 3.34(3H, s),                                                     3.77(4H, m), 6.32(1H, s)                               388  64      Oil       1.5-2.11(4H, m), 2.32(3H, s),                                                 2.37(3H, s), 2.6-3.1(3H, m),                                                  3.36(3H, s),                                                                  4.92(2H, br. d, J=12.6Hz),                                                    6.40(1H, s), 7.28(5H, br. s)                           396  52      Oil       1.3-2.0(4H, m), 2.22(3H, s),                                                  2.5-3.0(3H, m), 3.53(3H, s),                                                  4.64(2H, br. d, J=12.6Hz),                                                    6.05(1H, s), 7.1-7.6(10H, m)                           404  49      Oil       1.3-1.8(6H, m), 1.89(3H, s),                                                  3.40(3H, s), 3.63(4H, m),                                                     7.1-7.5(5H, m), 8.0(1H, s)                             412  28      Oil       1.5-2.1(4H, m), 2.0(3H, s),                                                   2.08(3H, s), 2.6-3.2(3H, m),                                                  3.20(3H, s),                                                                  4.85(2H, br. d, J=12.6Hz),                                                    7.27(5H, m), 8.26(1H, s)                               420  54      Oil       1.4-1.9(4H, m), 1.94(3H, s),                                                  2.5-3.05(3H, m), 3.42(3H, s),                                                 4.71(2H, br. d, J=12.6Hz),                                                    7.0-7.6(10H, m), 8.05(1H, s)                           428  55      Oil       1.3-2.1(4H, m), 2.5-3.0(3H, m),                                               3.51(3H, d, J=0.5Hz),                                                         4.60(1H, br. d, J=12.6Hz),                                                    7.0-7.6(10H, m),                                                              8.0(1H, d, J=2Hz)                                      600  67      Oil       1.2-1.7(6H, m), 3.12(4H, m),                                                  3.61(3H, s), 6.09(1H, d, J=7.2Hz),                                            7.1-7.5(5H, m),                                                               8.0(1H, d, J=7.2Hz)                                    608  57      Oil       0.5-1.0(2H, m),                                                               0.87(3H, d, J=5.2Hz),                                                         1.3-1.7(3H, m), 2.3-2.7(2H, m),                                               3.61(3H, s),                                                                  3.5-3.9(2H, br. d, J=12.6Hz),                                                 6.10(1H, d, J=7.2Hz),                                                         7.1-7.5(5H, m),                                                               8.0(1H, d, J=7.2Hz)                                    616  55      143-145   0.84(9H, s), 0.9-1.6(5H, m),                                                  2.44(2H, m), 3.61(3H, s),                                                     3.87(2H, br. d, J=12.6Hz).                                                    6.10(1H, d, J=5.2Hz),                                                         7.2-7.5(5H, m),                                                               8.0(1H, d, J=5.2Hz)                                    624  67      Oil       1.0-1.9(4H, m), 2.4-2.9(3H, m),                                               3.64(3H, s),                                                                  3.95(2H, br. d, J=12.6Hz),                                                    6.16(1H, d, J=5.2Hz),                                                         7.0-7.55(10H, m),                                                             8.07(1H, d, J=5.2Hz)                                   632  67      Oil       1.35(3H, t, J=7.2Hz),                                                         1.0-1.9(4H, m), 2.4-2.9(3H, m),                                               3.97(2H, br. d, J=12.6Hz),                                                    4.22(2H, q, J=7.2Hz),                                                         6.15(1H, d, J=7.2Hz),                                                         7.0-7.6(10H, m),                                                              8.05(1H, d, J=7.2Hz)                                   640  52      Oil       0.99(3H, t, J=7.2Hz),                                                         1.0-2.0(6H, m), 2.4-2.9(3H, m),                                               3.99(2H, br. d, J=12.9Hz),                                                    4.0-4.3(2H, m),                                                               6.15(1H, d, J=7.2Hz),                                                         7.0-7.6(10H, m),                                                              8.04(1H, d, J=7.2Hz)                                   648  63      Oil       1.0-2.0(4H, m), 1.46(3H, s),                                                  1.54(3H, s), 2.5-3.0(3H, m),                                                  4.15(2H, br. d, J=12.6Hz),                                                    5.13(1H, m),                                                                  6.19(1H, d, J=7.2Hz),                                                         7.0-7.6(10H, m),                                                              8.04(1H, d, J=7.2Hz)                                   658  88      Oil       1.0-1.85(4H, m), 2.4-2.80(3H, m),                                             3.95(2H, br. d, J=12.6Hz),                                                    5.38(2H, s),                                                                  6.10(1H, d, J=5.2Hz),                                                         7.0-7.60(15H, m),                                                             7.98(1H, d, J=5.2Hz)                                   664  71      160-162   1.0-2.0(4H, m), 2.4-2.9(3H, m),                                               3.62(3H, s),                                                                  3.99(2H, br. d, J=12.6Hz),                                                    6.16(1H, d, J=5.2Hz),                                                         7.0-7.5(9H, m),                                                               8.05(1H, d, J=5.2Hz)                                   672  60      153-154   1.0-2.0(4H, m), 2.5- 2.9(3H, m),                                              3.65(3H, s),                                                                  4.0(2H, br. d, J=12.6Hz),                                                     6.20(1H, d, J=7.2Hz),                                                         7.0-7.5(5H, m),                                                               7.56(2H, d, J=10.8Hz),                                                        8.01(1H, d, J=7.2Hz),                                                         8.14(2H, d, J=10.8Hz)                                  680  59      Oil       1.4-2.0(4H, m), 2.5-3.0(3H, m),                                               3.56(3H, s),                                                                  4.22(2H, br. d, J=12.6Hz),                                                    6.25(1H, d, J=5.2Hz),                                                         6.36(1H, dd, J=4.0, 1.0Hz),                                                   6.88(1H, d, J=4.0Hz),                                                         7.0-7.5(6H, m),                                                               8.08(1H, d, J=5.2Hz)                                   688  41      Oil       0.8-1.8(5H, m), 2.3-2.8(4H, m),                                               3.51(3H, s),                                                                  4.45(2H, br. d, J=12.6Hz),                                                    6.07(1H, d, J=5.2Hz),                                                         7.0-7.6(10H, m),                                                              8.02(1H, d, J=5.2Hz)                                   696  69       99-101   2.0(2H, m), 2.48(3H, s),                                                      2.79(2H, t, J=5.2Hz),                                                         3.48(3H, s),                                                                  3.97(2H, t, J=5.2Hz),                                                         6.80(1H, d, J=5.2Hz),                                                         7.0-7.5(4H, m),                                                               8.13(1H, d, J=5.2Hz)                                    252 38      Oil       1.3-2.0(4H, m), 2.4-3.0(3H, m),                                               3.47(3H, s),                                                                  4.59(2H, br. d, J=12.6Hz),                                                    6.47(1H, d, J=5.2Hz),                                                         7.0-7.6(9H, m),                                                               8.13(1H, d, J=5.2Hz)                                   284  38      136-138   1.2-2.0(4H, m), 2.4-3.0(3H, m),                                               3.53(3H, s),                                                                  4.59(2H, br. d, J=12.6Hz),                                                    6.15(1H, d, J=5.2Hz),                                                         6.95-7.60(14H, m),                                                            8.05(2H, d, J=5.2Hz)                                   137  95      Oil       0.88(3H, d, J=7Hz),                                                           1.1-2.8(7H, m),                                                               3.50(3H, s), 4.28(2H, m),                                                     6.03(1H, d, J=5Hz), 7.34(5H, m),                                              7.99(1H, d, J=5Hz)                                     145  38      Oil       0.7-2.8(12H, m), 3.49(3H, s),                                                 4.40(2H, m), 6.02(1H, d, J=5Hz),                                              7.32(5H, m), 7.96(1H, d, J=5Hz)                        147  96      Oil       0.88(6H, d, J=7Hz),                                                           1.0-2.9(8H, m), 3.50(3H, s),                                                  4.47(2H, m), 6.04(1H, d, J=5Hz),                                              7.34(5H, m), 8.00(1H, d, J=5Hz)                        153  38      Oil       1.04(3H, d, J=7Hz), 1.54(6H, m),                                              2.76(1H, m), 3.49(3H, s),                                                     4.28(1H, m), 4.70(1H, m),                                                     6.02(1H, d, J=5Hz), 7.32(5H, m),                                              7.98(1H, d, J=5Hz),                                    171-2                                                                              56      126-129   1.2-2.0(4H, m), 2.32(3H, s),                                                  2.5-3.0(3H, m), 3.52(3H, s),                                                  4.65(2H, br. d, J=12.6Hz),                                                    6.08(1H, d, J=5.2Hz),                                                         6.98-7.42(9H, m),                                                             8.01(1H, d, J=5.2Hz)                                  2000  95      Oil       0.87(6H, d, J=7Hz),                                                           1.1-3.4(6H, m), 3.50(3H, s),                                                  4.36(2H, m), 6.06(1H, d, J=5Hz),                                              7.36(5H, m), 8.02(1H, d, J=5Hz)                       2008  50      Oil       1.4-2.0(4H, m), 2.38(3H, s),                                                  2.5-3.1(3H, m), 3.44(3H, s),                                                  4.75(2H, br. d, J=12.6Hz),                                                    6.80(1H, d, J=5.2Hz),                                                         7.0-7.4(7H, m),                                                               7.66(2H, d, J=7.2Hz),                                                         8.09(1H, d, J=5.2Hz)                                  2048  37      Oil       8.00(1H, d, J=5Hz),                                                           7.2-7.5(5H, m),                                                               6.12(1H, d, J=5Hz),                                                           4.4-4.7(2H, m),                                                               3.50(3H, s), 1.1-3.0(17H, m)                          2056  89      Oil       8.00(1H, d, J=5Hz),                                                           7.2-7.5(5H, m),                                                               6.08(1H, d, J=5Hz),                                                           3.7-4.3(4H, m),                                                               3.50(3H, s), 2.9-3.3(2H, m),                                                  1.0-2.0(4H, m)                                        2064  47      Oil       8.00(1H, d, J=5Hz),                                                           7.2-7.6(5H, m),                                                               6.18(1H, d, J=5Hz),                                                           4.2-4.5(2H, m),                                                               3.60(3H, s), 1.0-4.0(12H, m)                          2074  35      Oil       8.12(2H, d, J=7Hz),                                                           7.88(1H, d, J=5Hz),                                                           7.35(1H, d, J=7Hz),                                                           6.22(1H, d, J=5Hz),                                                           7.2-7.6(5H, m), 4.8-5.0(2H, m),                                               3.64(3H, s), 2.7-3.1(2H, m),                                                  1.1-2.0(5H, m)                                        2080  16      Oil       8.02(1H, d, J=7Hz),                                                           7.2-7.6(5H, m),                                                               6.29(1H, d, J=7Hz),                                                           4.0-4.6(2H, m), 2.49(3H, s),                                                  0.8-3.2(14H, m)                                       2088  38      Oil       8.03(1H, d, J=7Hz),                                                           7.2-7.5(5H, m),                                                               6.28(1H, d, J=7Hz), 3.47(3H, s),                                              3.08(3H, s), 1.6-3.8(10H, m)                          2096  36      Oil       8.03(1H, d, J=5Hz),                                                           7.2-7.6(5H, m),                                                               6.58(1H, d, J=5Hz),                                                           4.5-4.8(2H, m),                                                               4.18(2H, q, J=7Hz), 1.50(3H, s),                                              1.5-3.0(7H, m),                                                               1.30(3H, t, J=2Hz)                                    2112  95      Oil       0.96(6H, s), 1.26(4H, m),                                                     3.48(3H, s), 3.50(4H, m),                                                     6.02(1H, d, J=5Hz), 7.32(5H, m),                                              7.98(1H, d, J=5Hz)                                    2120  44      Oil       0.85(3H, t, J=7Hz), 1.47(4H, m),                                              2.79(2H, m), 3.1-3.7(6H, m),                                                  6.08(1H, d, J=5Hz), 7.30(10H, m),                                             8.04(1H, d, J=5Hz)                                    2128  28      Oil       1.4-2.1(4H, m), 2.5-3.1(3H, m),                                               3.54(3H, s),                                                                  4.73(2H, br. d, J=12.6Hz),                                                    6.24(1H, d, J=5.4Hz),                                                         6.92(1H, dd, J=5.4, 3.6Hz),                                                   7.0-7.5(7H, m),                                                               8.08(1H, d, J=5.4Hz)                                  2136  93      Oil       1.3-2.0(4H, m), 2.45-3.0(3H, m),                                              3.52(3H, s),                                                                  4.48(2H, br. d, J=12.6Hz),                                                    6.13(1H, d, J=5.4Hz),                                                         7.0-7.4(6H, m), 7.75(1H, m),                                                  8.10(1H, d, J=5.4Hz),                                                         8.54(2H, m)                                           2144  53      Oil       8.00(1H, d, J=7Hz),                                                           7.2-7.5(5H, m),                                                               6.13(1H, d, J=7Hz),                                                           4.3-4.5(2H, m), 2.0-3.8(7H, m),                                               3.10(6H, s), 3.36(3H, s)                              2152  40      Oil       8.00(1H, d, J=7Hz),                                                           7.2-7.5(5H, m),                                                               6.38(1H, d, J=7Hz), 3.38(3H, s),                                              4.0-4.8(2H, m), 0.8-2.04(14H, m)                      2160  45      Oil       8.00(1H, d, J=5Hz),                                                           7.2-7.6(5H, m),                                                               6.10(1H, d, J=5Hz),                                                           4.1-4.4(2H, m), 3.58(3H, s),                                                  1.0-3.5(10H, m)                                       2170  42      Oil       1.2-3.1(7H, m), 3.51(3H, s),                                                  3.89(1H, m), 4.40(2H, m),                                                     6.19(1H, d, J=5Hz),                                                           7.2-7.9(10H, m),                                                              8.01(1H, d, J=5Hz),                                   2178  85      Oil       1.5-3.1(6H, m), 3.51(3H, s),                                                  3.90(1H, m), 4.74(2H, m),                                                     6.02(1H, d, J=5Hz),                                                           6.50(2H, d, J=8Hz), 7.24(7H, m),                                              7.96(1H, d, J=8Hz)                                    2184  56      Oil       (CDCl.sub.3 --CD.sub.3 OD)                                                    1.2-3.3(7H, m), 3.50(3H, s),                                                  4.46(2H, m), 6.20(1H, d, J=5Hz),                                              7.36(5H, m), 8.01(1H, d, J=5Hz)                       2192  50      Oil       1.4- 3.3(6H, m), 3.56(3H, s),                                                 4.2-4.7(3H, m),                                                               6.60(1H, d, J=7Hz),                                                           7.1-7.9(14H, m),                                                              7.96(1H, d, J=7Hz)                                    2198  42      Oil       (CDCl.sub.3 --CD.sub.3 OD)                                                    1.4-3.3(7H, m), 3.53(3H, s),                                                  4.42(2H, m), 6.72(1H, d, J=7Hz),                                              7.3-7.9(10H, m),                                                              7.98(1H, d, J=7Hz)                                    2206  45      Oil       1.61(6H, br. s), 1.4-2.1(4H, m),                                              2.55-3.15(3H, m), 3.22(3H, s),                                                3.40(4H, br. s),                                                              4.87(2H, br. d, J=12.6Hz),                                                    5.97(1H, d, J=5.2Hz),                                                         7.24(5H, m),                                                                  8.0(1H, d, J=5.2Hz)                                   2214  26      131-132   1.5-2.2(4H, m), 2.5-3.3(3H, m),                                               3.40(3H, s),                                                                  4.80(2H, br. d, J=12.6Hz),                                                    6.16(1H, d, J=5.2Hz),                                                         6.89-7.65(10H, m),                                                            8.20(1H, d, J=5.2Hz),                                                         12.23(1H, br, s)                                      2222  60      46-49     7.9-8.1(3H, m), 7.2-7.6(8H, m),                                               6.10(1H, d, J=5Hz),                                                           5.0-5.2(1H, m),                                                               3.8-4.1(2H, m), 3.50(3H, s),                                                  1.8-2.0(6H, m)                                        2230  97      Oil       1.26-2.10(4H, m), 2.30(3H, s),                                                2.39(4H, m), 2.5-3.20(3H, m),                                                 3.21(3H, s), 3.47(4H, m),                                                     4.85(2H, br. d, J=12.6Hz),                                                    5.96(1H, d, J=5.2Hz),                                                         7.20(5H, m),                                                                  8.0(1H, d, J=5.2Hz)                                   2238  69      Oil       1.35(3H, t, J=7.2Hz),                                                         1.4-2.15(4H, m),                                                              2.55-3.20(3H, m), 3.44(3H, s),                                                4.25(2H, q, J=7.2Hz),                                                         4.86(2H, br. d, J=12.6Hz),                                                    7.23(6H, m), 8.12(1H, d, J=5.2Hz)                     2246  13      Oil       1.2-3.4(7H, m), 3.56(3H, s),                                                  3.92(2H, s), 4.74(2H, m),                                                     6.50(1H, d, J=7Hz), 7.18(10H, m),                                             8.18(1H, d, J=7Hz)                                    2254  45      Oil       0.94(3H, t, J=7Hz), 1.52(6H, m),                                              2.02(2H, m), 2.79(4H, m),                                                     3.50(3H, s), 4.50(2H, m),                                                     5.04(2H, m), 6.09(1H, d, J=7Hz),                                              7.36(5H, m), 7.98(1H, d, J=7Hz)                       2264  90      Oil       1.1-1.6(4H, m), 2.4-2.9(3H, m),                                               3.46(3H, s), 4.50(2H, m),                                                     6.06(1H, d, J=5Hz), 7.28(15H, m),                                             7.94(1H, d, J=5Hz)                                    2274  62      112-115   1.35-2.10(4H, m),                                                             2.50-3.10(3H, m),                                                             3.0(3H, s), 4.74(2H, s),                                                      4.88(2H, br. d, J=12.6Hz),                                                    5.79(1H, d, J=5.2Hz),                                                         7.22(10H, m),                                                                 7.90(1H, d, J=5.2Hz)                                  2282  67      Oil       1.45-2.15(4H, m),                                                             2.55-3.20(3H, m), 3.40(3H, s),                                                4.82(2H, br. d, J=12.6Hz),                                                    5.05(2H, s),                                                                  6.37(1H, d, J=5.2Hz),                                                         6.70-7.10(3H, m),                                                             7.10-7.45(7H, m),                                                             8.25(1H, d, J=5.2Hz)                                  2290  42      Oil       1.4-2.1(4H, m), 2.96(6H, s),                                                  2.58-3.20(3H, m), 3.20(3H, s),                                                4.85(2H, br. d, J=12.6Hz),                                                    5.92(1H, d, J=5.2Hz),                                                         7.22(5H, m),                                                                  8.02(1H, d, J=5.2Hz)                                  2298  56      Oil       1.15(6H, m), 1.4-2.1(4H, m),                                                  2.5-3.2(3H, m), 3.18(3H, s),                                                  3.35(4H, m),                                                                  4.88(2H, br. d, J=12.6Hz),                                                    5.90(1H, d, J=5.2Hz),                                                         7.22(5H, m),                                                                  7.98(1H, d, J=5.2Hz)                                  2306  75      Oil       1.76(4H, m), 2.92(2H, m),                                                     3.36(1H, m), 3.51(3H, s),                                                     4.52(2H, m), 6.52(1H, d, J=7Hz),                                              7.39(7H, m), 7.86(2H, d, J=7Hz),                                              8.02(1H, d, J=7Hz)                                    2314  26      Oil       1.2-2.0(4H, m), 2.1-2.9(3H, m),                                               3.90(3H, s), 4.32(2H, m),                                                     6.70(1H, d, J=7Hz),                                                           7.0-7.7(10H, m),                                                              8.23(1H, d, J=7Hz)                                    2322  77      Oil       1.4-2.1(4H, m), 2.5-3.4(3H, m),                                               3.24(3H, s), 3.57(8H, m),                                                     4.88(2H, br. d, J=12.6Hz),                                                    6.0(1H, d, J=5.4Hz), 7.23(5H, m),                                             8.04(1H, d, J=5.4Hz)                                  2330  59      119-121   1.4-2.1(4H, m), 2.6-3.2(3H, m),                                               3.61(3H, s),                                                                  4.89(2H, br. d, J=12.6Hz),                                                    7.0-7.5(11H),                                                                 8.16(1H, d, J=5.4Hz)                                  2338  23      Oil       8.02(1H, d, J=7Hz),                                                           7.2-7.6(5H, m),                                                               6.38(1H, d, J=7Hz), 3.36(3H, s),                                              1.0-3.5(13H, m)                                       2346  54      Oil       8.00(1H, d, J=7Hz),                                                           7.2-7.9(10H, m),                                                              6.48(1H, d, J=7Hz),                                                           4.2-4.5(2H, m),                                                               3.38(3H, s), 1.4-3.8(7H, m)                           2016  50      Oil       1.4-2.0(4H, m), 2.5-3.0(3H, m),                                               3.53(3H, s),                                                                  4.21(2H, br. d, J=12.6Hz),                                                    6.12(1H, d, J=7.2Hz),                                                         6.35(1H, d, J=7.2Hz),                                                         7.0-7.5(11H, m)                                       2024  36      Oil       1.4-2.0(4H, m), 2.5-3.1(3H, m),                                               3.54(3H, s),                                                                  4.25(2H, br. d, J=12.6Hz),                                                    7.0-7.6(10H, m), 7.41(1H, s),                                                 7.79(1H, s)                                           2032  69      76-82     1.2-2.0(8H, m), 2.4-3.9(6H, m),                                               3.56(3H, s), 4.50(4H, m),                                                     7.0-7.52(15H, m)                                      2040  28      Oil       1.4-2.1(4H, m), 2.5-3.2(3H, m),                                               3.50(3H, s),                                                                  4.38(2H, br. d, J=12.6Hz),                                                    6.32(1H, dd, J=3.6, 2.0Hz),                                                   6.71(1H, dd, J=3.0, 1.0Hz),                                                   7.24(6H, m), 7.58(1H, s),                                                     7.93(1H, s)                                            154-1                                                                              61      Oil       1.4-2.2(4H, m), 2.6-3.2(3H, m),                                               3.36(3H, s), 3.43(3H, s),                                                     4.43(2H, s),                                                                  4.84(2H, br. d, J=12.6Hz),                                                    6.44(1H, d, J=5.2Hz),                                                         7.22(5H, m),                                                                  8.22(1H, d, J=5.2Hz)                                   171-4                                                                              64      Oil       1.37(3H, t, J=7.2Hz),                                                         1.4-2.1(4H, m), 2.5-3.05(3H, m),                                              3.52(3H, s),                                                                  3.98(2H, q, J=7.2Hz),                                                         4.69(2H, br. d, J=12.6Hz),                                                    6.03(1H, d, J=5.2Hz),                                                         6.76(2H, m), 7.0-7.6(7H, m),                                                  8.0(1H, d, J=5.2Hz)                                    297  60      Oil       1.80(4H, m), 2.90(3H, m),                                                     4.92(2H, m), 6.64(1H, d, J=5Hz),                                              7.20(5H, m), 7.80(4H, m),                                                     8.39(1H, d, J=5Hz)                                     305  90      Oil       1.76(4H, m), 2.90(2H, m),                                                     3.40(1H, m), 3.51(3H, s),                                                     4.49(2H, m), 6.11(1H, d, J=5Hz),                                              7.40(8H, m), 7.92(2H, m),                                                     8.01(1H, d, J=5Hz)                                     307  19      Oil       8.01(1H, d, J=7Hz),                                                           7.2-7.6(5H, m),                                                               6.10(1H, d, J=7Hz),                                                           4.2-4.4(2H, m), 1.2-3.8(10H, m),                                              3.35(3H, s)                                            241  69      Oil       1.1-2.1(4H, m), 2.5-3.0(3H, m),                                               3.50(3H, s),                                                                  4.60(2H, br. d, J=12.6Hz),                                                    6.04(1H, d, J=5.2Hz),                                                         6.8-7.7(9H, m),                                                               8.04(1H, d, J=5.2Hz)                                  2022  84      Oil       1.4-2.0(4H, m), 2.45-3.0(3H, m),                                              3.52(3H, s),                                                                  4.20(2H, br. d, J=12.6Hz),                                                    6.10(1H, d, J=7.2Hz),                                                         6.35(1H, d, J=7.2Hz),                                                         7.0-7.4(10H, m)                                       2023  85      112-114   1.3-2.1(4H, m), 2.5-3.2(3H, m),                                               3.47(3H, s),                                                                  4.35(2H, br. d, J=12.6Hz),                                                    6.31(1H, d, J=7.2Hz),                                                         6.50(1H, d, J=7.2Hz),                                                         6.65-7.6(9H, m, J=7.2Hz)                               149  87      103-105   0.5-1.8(5H, m),                                                               0.88(3H, d, J=5.2Hz),                                                         2.3-2.8(2H, m),                                                               4.15(2H, br. d, J=12.6Hz),                                                    6.06(1H, d, J=5.2Hz),                                                         7.1-7.8(10H, m),                                                              8.08(1H, d, J=5.2Hz)                                   171-8                                                                              79      Oil       1.2-2.0(4H, m), 2.4-3.0(3H, m),                                               3.52(3H, s),                                                                  4.51(2H, br. d, J=12.6Hz),                                                    6.32(1H, d, J=5.2Hz),                                                         6.76-7.65(9H, m),                                                             8.1(1H, d, J=5.2Hz)                                    171-10                                                                             62      Oil       1.2-2.1(4H, m), 2.5-3.0(3H, m),                                               3.49(3H, s),                                                                  4.53(2H, br. d, J=12.6Hz),                                                    6.36(1H, d, J=5.2Hz),                                                         7.0-7.5(8H, m),                                                               8.12(1H, d, J=5.2Hz)                                   171-1                                                                              26      Oil       1.3-2.1(4H, m), 2.5-3.0(3H, m),                                               3.47(3H, s),                                                                  4.85(2H, d, J=12.6Hz),                                                        6.35(1H, d, J=5.2Hz),                                                         6.90(1H, d, J=15.4Hz),                                                        7.0-7.6(10H, m),                                                              7.65(1H, d, J=15.4Hz),                                                        8.20(1H, d, J=5.2Hz)                                   171-6                                                                              41      Oil       1.4-2.0(4H, m), 2.34(3H, s),                                                  2.5-3.0(3H, m), 3.46(3H, s),                                                  4.64(2H, br. d, J=12.6Hz),                                                    6.32(1H, d, J=5.2Hz),                                                         7.0-7.4(9H, m),                                                               8.04(1H, d, J=5.2Hz)                                   171-12                                                                             71      113-116   1.1-2.1(4H, m), 2.4-3.0(3H, m),                                               3.49(3H, s),                                                                  4.51(2H, br. d, J=12.6Hz),                                                    6.1(1H, d, J=5.2Hz),                                                          7.0-7.7(8H, m),                                                               8.1(1H, d, J=5.2Hz)                                   ______________________________________                                    

EXAMPLE 2 4-(N-methylbenzamino)-2-(4-phenylpiperidino)pyrimidinep-toluenesulfonate (compound No. 168)

A solution of 3.0 g (0.022 mole) of p-toluenesulfonic acid monohydratein 300 ml of ethyl acetate was slowly added at room temperature to asolution of 6.0 g (0.022 mole) of4-(N-methylbenzamino)-2-(4-phenylpiperidino)pyrimidine in 100 ml ofethyl acetate. As soon as the addition was effected, a suspension wasformed. After the end of the addition, the suspension was stirred for 10minutes. The resulting solid was separated by filtration, washed withethyl acetate and ether, and dried to give 6.8 g (yield 83%) of thedesired compound.

Melting point: 180°-182° C.

¹ H-NMR spectrum (deuterochloroform, δppm): 1.4-2.1(4H, m), 2.35(3H, s),2.6-3.3(3H, m), 3.56(3H, s), 4.55(2H, br. d, J=12.6 Hz), 6.60(1H, d,J=7.2 Hz), 7.0-7.9(14H, m), 8.36 (1H, d, J=7.2 Hz).

In the same way as above, the following compounds were produced andtheir data are shown in Table 4.

                                      TABLE 4                                     __________________________________________________________________________    Com-      Melting                                                             pound Yield                                                                             point   .sup.1 H-NMR spectrum                                       No.   (%) (°C.)                                                                          (CDCl.sub.3 solution, δppm)                           __________________________________________________________________________     104  100 54-58   2.33(3H, s), 2.8-3.5(6H, m),                                                  3.50(3H, s), 6.64(1H, d, J=7.2Hz)                                             7.13(2H, d, J=7.2Hz), 7.50(5H, m,),                                           7.75(2H, d, J=7.2Hz)                                                          8.24(1H, d, J=7.2Hz)                                         112  100 Oil     0.90(6H, m), 1.0-1.8(8H, m),                                                  2.35(3H, s), 3.2-3.7(4H, m),                                                  3.5(3H, s), 6.58(1H, d, J=7.2Hz),                                             7.13(2H, d, J=7.2Hz),                                                         7.3-7.7(5H, m),                                                               7.76(2H, d, J=7.2Hz)                                                          8.36(1H, d, J=7.2Hz)                                         120  82  125-126 2.0(4H, m), 2.35(3H, s),                                                      3.44(2H, m), 3.52(3H, s),                                                     3.72(2H, m), 6.56(1H, d, J=7.2Hz),                                            7.15(2H, d, J=7.2Hz),                                                         7.2-7.7(5H, m),                                                               7.78(2H, d, J=7.2Hz),                                                         8.22(1H, d, J=7.2Hz)                                         128  90  149-150 1.72(6H, br. s), 2.37(3H, s),                                                 2.48(3H, s), 3.50(3H, s),                                                     3.84(4H, br. s),                                                              7.18(2H, d, J=7.5Hz),                                                         7.44(1H, d, J=7.2Hz),                                                         7.81(2H, d, J=7.5Hz),                                                         8.38(1H, d, J=7.2Hz)                                         136  79  48-52   1.63(6H, br. s), 2.36(3H, s),                                                 3.52(3H, s), 3.64(4H, br, s),                                                 6.56(1H, d, J=7.2Hz),                                                         7.16(2H, d, J=7.2Hz), 7.55(5H, m),                                            7.79(2H, d, J=7.2Hz),                                                         8.30(1H, d, J=7.2Hz)                                         144  90  49-51   0.94(3H, d, J=5.2Hz),                                                         0.8-1.90(5H, m), 2.36(3H, s),                                                 2.8-3.2(2H, m), 3.52(3H, s),                                                  4.32(2H, br. d, J=12.6Hz),                                                    6.6(1H, d, J=7.2Hz),                                                          7.16(2H, d, J=7.2Hz),                                                         7.3-7.7(5H, m),                                                               7.8(2H, d, J=7.2Hz),                                                          8.3(1H, d, J=7.2Hz)                                          152  72  52-56   0.85(9H, s), 1.0-2.0(5H, m),                                                  2.36(3H, s), 2.5-3.2(2H, m),                                                  3.52(3H, s),                                                                  4.44(2H, br. d, J=12.6Hz),                                                    6.58(1H, d, J=7.2Hz),                                                         7.16(2H, d, J=7.2Hz),                                                         7.3-7.7(5H, m), 7.8(2H, d, J=7.2Hz)                                           8.28(1H, d, J=7.2Hz)                                         160  80  206-207 1.3-2.1(4H, m), 2.32(3H, s),                                                  2.5-3.3(3H, m),                                                               4.76(2H, br. d, J=12.6Hz),                                                    7.0-8.4(16H, m)                                              176  75  68-72   1.36(3H, t, J=7.2Hz),                                                         1.4-2.1(4H, m), 2.33(3H, s),                                                  2.5-3.3(3H, m),                                                               4.12(2H, q, J=7.2Hz),                                                         4.42(2H, br. d, J=12.6Hz),                                                    6.34(1H, d, J=7.2Hz),                                                         7.0-7.9(12H, m),                                                              8.32(1H, d, J=7.2Hz)                                         184  85  53-57   1.0(3H, t, J=7.2Hz), 1.4-2.1(6H, m)                                           2.35(3H, s), 2.5-3.3(3H, m),                                                  4.04(2H, m),                                                                  4.42(2H, br. d, J=12.6Hz),                                                    6.28(1H, d, J=7.2Hz),                                                         7.0-7.7(14H, m),                                                              8.35(1H, d, J=7.2Hz)                                         192  80  59-62   1.2-2.0(4H, m), 2.31(3H, s),                                                  2.5-3.2(3H, m), 4.34(2H, m),                                                  5.28(2H, s), 6.33(1H, d, J=7.2Hz),                                            7.0-7.8(19H, m),                                                              8.25(1H, d, J=7.2Hz)                                         200  79   98-105 1.4-2.0(4H, m), 2.32(6H, s),                                                  2.5-3.2(3H, m), 2.92(3H, s),                                                  2.98(3H, s), 2.98(3H, s),                                                     3.50(2H, m),                                                                  4.40(2H, br. d, J=12.6Hz),                                                    4.60(2H, m), 6.40(1H, d, J=5.2Hz),                                            7.0-7.8(18H, m),                                                              8.10(1H, d, J=5.2Hz), 10.80(1H, m)                           208  90  172-174 1.6-2.2(4H, m), 2.35(3H, s),                                                  2.48(3H, s), 2.6-3.5(3H, m),                                                  3.52(3H, s),                                                                  4.77(2H, br. d, J=12.6Hz),                                                    7.1-7.9(10H, m),                                                              8.42(1H, d, J=7.2Hz)                                         216  86  154-156 1.24(6H, d, J-7.0Hz),                                                         1.4-2.2(4H, m), 2.32(3H, s),                                                  2.6-3.4(4H, m), 3.51(3H, s),                                                  4.75(2H, br. d, J=12.6Hz),                                                    7.12(2H, d, J=7.2Hz), 7.20(5H, m),                                            7.36(1H, d, J=7.2Hz),                                                         7.76(2H, d, J=7.2Hz),                                                         8.34(1H, d, J=7.2Hz)                                         224  86  158-160 1.40(9H, s), 1.5-2.2(4H, m),                                                  2.34(3H, s), 2.6-3.3(3H, m),                                                  3.38(3H, s),                                                                  4.76(2H, br. d, J=12.6Hz),                                                    6.56(1H, d, J=7.2Hz),                                                         7.0-7.4(7H, m),                                                               7.82(2H, d, J=7.2Hz)                                                          8.30(1H, d, J=7.2Hz)                                         232  100 49-52   1.0-2.3(14H, m), 2.33(3H, s),                                                 2.6-3.5(4H, m), 3.48(3H, s),                                                  4.75(2H, br. d, J=12.6Hz),                                                    7.12(2H, d, J=7.2Hz),                                                         7.0-7.5(6H, m),                                                               7.76(2H, d, J=7.2Hz),                                                         8.32(1H, d, J=7.2Hz)                                         240  77  132-134 1.4-2.1(4H, m), 2.36(3H, s),                                                  2.6-3.3(3H, m), 3.55(3H, s),                                                  4.52(2H, br. d, J=12.6Hz),                                                    6.67(1H, d, J=7.2Hz),                                                         7.16(2H, d, J=7.2Hz),                                                         7.0-7.7(9H, m),                                                               7.81(2H, d, J=7.2Hz),                                                         8.44(1H, d, J=7.2Hz)                                         248  84  168-170 1.2-2.1(4H, m), 2.32(3H, s),                                                  2.5-3.4(3H, m), 3.51(3H, s),                                                  4.48(2H, br. d, J=12.6Hz),                                                    6.69(1H, d, J=7.2Hz),                                                         7.12(2H, d, J=7.2Hz),                                                         7.0-7.65(9H, m),                                                              7.76(2H, d, J=7.2Hz),                                                         8.40(1H, d, J=7.2Hz)                                         264  95  189-190 1.2-2.0(4H, m), 2.34(3H, s),                                                  2.5-3.3(3H, m), 3.55(3H, s),                                                  4.40(2H, br. d, J=12.6Hz),                                                    6.85(1H, d, J=7.2Hz),                                                         7.0-7.5(7H, m),                                                               7.77(4H, d, J=7.2Hz),                                                         8.31(2H, d, J=7.2Hz),                                                         8.52(1H, d, J=7.2Hz)                                         272  84  56-60   1.4-2.0(4H, m), 2.33(3H, s),                                                  2.6-3.25(3H, m), 3.54(3H, s),                                                 3.84(3H, s),                                                                  4.65(2H, br. d, J=12.6Hz),                                                    6.38(1H, d, J=7.2Hz),                                                         6.92(2H, d, J=8.5Hz), 7.23(7H, m),                                            7.59(2H, d, J=8.5Hz),                                                         7.80(2H, d, J=7.2Hz),                                                         8.22(1H, d, J=7.2Hz)                                         280  91  174-76  1.4-2.2(4H, m), 2.32(3H, s),                                                  2.5-3.4(3H, m), 3.51(3H, s),                                                  3.86(6H, s), 3.91(3H, s),                                                     4.65(2H, br. d, J=12.6Hz),                                                    6.69(1H, d, J=7.2Hz), 6.85(2H, s),                                            7.0-7.4(7H, m), 7.76(2H, s),                                                  8.30(1H, d, J=7.2Hz)                                         296  91  174-78  1.4-2.2(4H, m), 2.35(3H, s),                                                  2.6-3.3(3H, m), 3.58(3H, s),                                                  4.69(2H, br. d, J=12.6Hz),                                                    6.55(1H, d, J=7.2Hz), 6.60(1H, m),                                            7.0-7.5(8H, m), 7.56(1H, m),                                                  7.8(2H, d, J=7.2Hz),                                                          8.36(1H, d, J=7.2Hz)                                         304  100 54-58   0.8-2.0(5H, m), 2.33(3H, s),                                                  2.51(2H, d, J=7.2Hz),                                                         2.6-3.2(2H, m), 3.49(3H, s),                                                  4.35(2H, br. d, J=12.6Hz),                                                    6.57(1H, d, J=7.2Hz),                                                         7.0-7.9(14H, m),                                                              8.28(1H, d, J=7.2Hz),                                        312  78  182-184 2.37(3H, s), 2.51(3H, s),                                                     3.01(2H, t, J=5.2Hz), 3.57(3H, s),                                            4.04(2H, t, J=5.2Hz), 4.95(2H, s),                                            7.20(2H, d, J=7.2Hz), 7.25(4H, s),                                            7.54(1H, d, J=7.2Hz),                                                         7.94(2H, d, J=7.2Hz),                                                         8.40(1H, d, J=7.2Hz)                                         320  81  49-51   1.9-2.3(2H, m), 2.36(3H, s),                                                  2.40(3H, s), 2.72(2H, t, J=5.2Hz),                                            3.38(3H, s), 4.04(2H, t, J=5.2Hz),                                            7.20(5H, m), 7.50(1H, m),                                                     7.76(3H, m), 8.53(1H, d, J=5.2Hz)                            328  75  136-138 2.04(2H, q, J= 5.2Hz), 2.38(3H, s),                                           2.73(2H, t, J=5.2Hz), 3.43(3H, s),                                            3.99(2H, t, J=5.2Hz),                                                         6.88(1H, d, J=7.2Hz), 7.20(5H, m),                                            7.50(6H, m), 7.80(2H, d, J=7.2Hz),                                            8.50(1H, d, J=7.2Hz)                                         336  100 58-62   2.36(3H, s), 3.52(3H, s),                                                     3.68(8H, br. s),                                                              6.69(1H, d, J=7.0Hz)                                                          7.15(2H, d, J=7.2Hz), 7.52(5H, m),                                            7.75(2H, d, J=7.2Hz),                                                         8.28(1H, d, J=7.0Hz)                                         344  100 164-168 2.39(3H, s), 3.10(4H, m),                                                     3.48(3H, s), 3.83(4H, m),                                                     6.28(1H, d, J=5.2Hz),                                                         7.20(2H, d, J=7.2Hz), 7.35(5H, m),                                            7.73(2H, d, J=7.2Hz),                                                         8.05(1H, d, J=5.2Hz),                                        352  100 58-60   2.36(3H, s), 2.83(3H, s),                                                     2.98(4H, m), 3.49(3H, s),                                                     3.90(4H, m), 6.33(1H, d, J=5.2Hz),                                            7.15(2H, d, J=7.2Hz),                                                         7.0-7.5(5H, m),                                                               7.75(2H, d, J=7.2Hz),                                                         8.06(1H, d, J=5.2Hz)                                         360  100 52-56   2.34(3H, s), 3.32(4H, br. s),                                                 3.49(3H, s), 4.0(4H, br. s),                                                  6.68(1H, d, J=7.2Hz),                                                         7.0-7.8(14H, m),                                                              8.22(1H, d, J=7.2Hz)                                         368  82  66-72   2.38(3H, s), 3.05(4H, m),                                                     3.46(3H, s), 4.0(4H, m),                                                      4.25(2H, s), 6.32(1H, d, J=5.2Hz),                                            7.17(2H, d, J=7.2Hz), 7.40(10H, m),                                           7.79(2H, d, J=7.2Hz),                                                         8.05(1H, d, J=5.2Hz)                                         376  91  120-125 2.36(3H, s), 2.94(4H, m),                                                     3.44(3H, s), 4.0(4H, m), 5.0(1H, m)                                           6.40(1H, d, J=5.2Hz),                                                         7.0-7.9(18H, m),                                                              8.05(1H, d, J=5.2Hz)                                         384  80  157-158 1.67(6H, br. s), 2.31(3H, s),                                                 2.46(3H, s), 2.71(3H, s),                                                     3.48(3H, s), 3.76(4H, m),                                                     6.33(1H, s), 7.14(2H, d, J=7.2Hz),                                            7.80(2H, d, J=7.2Hz)                                         392  85  159-161 1.6-2.2(4H, m), 2.34(3H, s),                                                  2.48(3H, s), 2.71(3H, s),                                                     2.7-3.4(3H, m), 3.50(3H, s),                                                  4.87(2H, br. d, J=12.6Hz),                                                    7.14(2H, d, J=7.2Hz), 7.30(6H, m),                                            7.80(2H, d, J=7.2Hz)                                         400  94  60-65   1.4-2.1(4H, m), 2.32(3H, s),                                                  2.64(3H, s), 2.6-3.3(3H, m),                                                  3.52(3H, s),                                                                  4.64(2H, br. d, J=12.6Hz),                                                    6.51(1H, s), 7.15(2H, d, J=7.2Hz),                                            7.0-7.7(10H, m),                                                              7.80(2H, d, J=7.2Hz)                                         408  83  50-55   1.64(6H, br. s),                                                              2.04(3H, d, J=1.0Hz), 2.39(3H, s),                                            3.48(3H, s), 3.70(4H, br. s),                                                 7.20(2H, d, J=7.2Hz), 7.52(5H, m),                                            7.80(2H, d, J=7.2Hz), 8.33(1H, s)                            416  80  58-62   1.6-2.2(4H, m), 2.09(3H, m),                                                  2.29(3H, s), 2.35(3H, s),                                                     2.6-3.5(3H, m), 3.36(3H, s),                                                  4.79(2H, br. d, J=12.6Hz),                                                    7.18(2H, d, J=7.2Hz), 7.30(5H, m),                                            7.84(2H, d, J=7.2Hz), 8.46(1H, s),                           424  94  68-72   1.4-2.2(4H, m), 2.06(3H, s),                                                  2.35(3H, s), 2.6-3.4(3H, m),                                                  3.49(3H, s),                                                                  4.62(2H, br. d, J=12.6Hz),                                                    7.0-7.7(12H, m),                                                              7.81(2H, d, J=8.5Hz), 8.37(1H, s)                            432  80  146-148 1.3-2.2(4H, m), 2.36(3H, s),                                                  2.5-3.4(3H, m),                                                               3.58(3H, d, J=1.0Hz),                                                         4.56(2H, br. d, J=12.6Hz),                                                    7.0-7.9(14H, m),                                                              8.44(1H, d, J=5.2Hz)                                         604  100 44-48   1.2-1.8(6H, m), 2.36(3H, s),                                                  3.28(4H, m), 3.64(3H, s),                                                     6.50(1H, dd. J=7.2, 1.5Hz),                                                   7.20(2H, d, J=7.2Hz),                                                         7.2-7.6(5H, m),                                                               7.85(2H, d, J=7.2Hz)                                                          8.39(1H, d, J=7.2Hz)                                         612  100 44-48   0.5-1.1(2H, m),                                                               0.89(3H, d, J=5.2Hz),                                                         1.4-1.8(3H, m), 2.36(3H, s),                                                  2.3-2.9(2H, m), 3.64(3H, s),                                                  3.85(2H, br. d, J=12.6Hz),                                                    6.53(1H, d, J=7.2Hz),                                                         7.19(2H, d, J=7.2Hz),                                                         7.2-7.6(5H, m),                                                               7.84(2H, d, J=7.2Hz),                                                         8.36(1H, d, J=7.2Hz)                                         620  84  106-110 0.82(9H, s), 0.9-1.8(5H, m),                                                  2.0-3.0(2H, m), 2.36(3H, s),                                                  3.61(3H, s),                                                                  4.0(2H, br. d, J=12.6Hz),                                                     6.72(1H, d, J=7.2Hz),                                                         7.18(2H, d, J=7.2Hz),                                                         7.2-7.6(5H, m),                                                               7.84(2H, d, J=7.2Hz),                                                         8.42(1H, d, J=7.2Hz)                                         628  84  160-161 1.0-2.0(4H, m), 2.35(3H, s),                                                  2.4-3.2(3H, m), 3.64(3H, s),                                                  4.05(2H, br. d, J=12.6Hz),                                                    6.72(1H, d, J=7.2Hz),                                                         7.0-7.6(12H, m),                                                              7.84(2H, d, J=7.2Hz),                                                         8.49(1H, d, J=7.2Hz)                                         636  83  143-147 1.30(3H, t, J=7.2Hz),                                                         1.0-2.0(4H, m), 2.35(3H, s),                                                  2.4-3.3(3H, m),                                                               4.10(2H, br. d, J=12.6Hz),                                                    4.17(2H, q, J=7.2Hz),                                                         6.80(1H, d, J=7.2Hz)                                                          7.0-7.6(12H, m),                                                              7.84(2H, d, J=7.2Hz),                                                         8.48(1H, d, J=7.2Hz)                                         644  96  178-180 0.95(3H, t, J=7.2Hz),                                                         1.4-2.1(6H, m), 2.37(3H, s),                                                  2.5-3.3(3H, m), 3.9-4.3(4H, m),                                               6.67(1H, d, J=7.2Hz),                                                         7.0-8.0(14H, m),                                                              8.55(1H, d, J=7.2Hz)                                         652  87  66-68   1.0-2.0(4H, m), 1.44(3H, s),                                                  1.52(3H, s), 2.36(3H, s),                                                     2.5-3.3(3H, m), 3.9-4.5(2H, m),                                               4.76(1H, m), 6.78(1H, d, J=7.2Hz),                                            7.0-7.7(12H, m),                                                              7.83(2H, d, J=7.2Hz),                                                         8.39(1H, d, J=7.2Hz)                                         660  91  116-120 1.2-2.0(4H, m), 2.33(3H, s),                                                  2.4-3.2(3H, m),                                                               4.04(2H, br. d, J=12.6Hz),                                                    5.36(2H, s), 6.56(1H, d, J=7.2Hz),                                            6.9-7.9(19H, m),                                                              8.38(1H, d, J=7.2Hz)                                         668  82  173-175 0.9-2.0(4H, m), 2.35(3H, s),                                                  2.4-3.3(3H, m), 3.6(3H, s),                                                   4.12(2H, br. d, J=12.6Hz),                                                    6.82(1H, d, J=7.2Hz)                                                          7.0-7.9(13H, m),                                                              8.45(1H, d, J=7.2Hz)                                         676  79  199-200 1.0-2.0(4H, m), 2.36(3H, s),                                                  2.5-3.2(3H, m), 3.64(3H, s),                                                  4.14(2H, br. d, J=12.6Hz),                                                    6.80(1H, d, J=7.2Hz)                                                          6.95-7.50(7H, m), 7.76(4H, m),                                                8.20(2H, d, J=7.2Hz),                                                         8.46(1H, d, J=7.2Hz)                                          684 86  60-66   1.3-2.1(4H, m), 2.33(3H, s),                                                  2.5-3.3(3H, m), 3.60(3H, s),                                                  4.30(2H, br. d, J=12.6Hz),                                                    6.48(1H, dd. J=4.0, 1.0Hz),                                                   6.87(1H, d, J=7.2Hz)                                                          7.0-7.5(9H, m),                                                               7.82(2H, d, J=7.2Hz),                                                         8.52(1H, d, J=7.2Hz)                                         692  100 56-60   0.3-1.9(5H, m), 2.33(3H, s),                                                  2.44(2H, d, J=7.2Hz),                                                         2.2-3.1(2H, m), 3.57(3H, s),                                                  3.89(2H, br. d, J=12.6Hz),                                                    6.64(1H, d, J=7.2Hz),                                                         6.9-7.9(14H, m),                                                              8.40(1H, d, J=7.2Hz)                                         700  96  136-138 2.5(2H, q, J=5.2Hz), 2.32(3H, s),                                             2.51(3H, s), 2.79(2H, t, J=5.2Hz),                                            3.58(3H, s), 4.04(2H, t, J=5.2Hz),                                            6.95(1H, d, J=7.2Hz),                                                         7.11(2H, d, J=7.0Hz), 7.30(4H, s),                                            7.78(2H, d, J=7.2Hz),                                                         8.58(1H, d, J=7.2Hz)                                         256  100 65-70   1.2-2.2(4H, m), 2.34(3H, s),                                                  2.5-3.4(3H, m), 3.46(3H, s),                                                  4.5(2H, br. d, J=12.6Hz),                                                     6.9-7.6(12H, m),                                                              7.78(2H, d, J=7.2Hz),                                                         8.40(1H, d, J=7.2Hz)                                         288  100 80-85   1.2-2.0(4H, m), 2.32(3H, s),                                                  2.5-3.3(3H, m), 3.55(3H, s),                                                  4.47(2H, br. d, J=12.6Hz),                                                    6.62(1H, d, J=7.2Hz)                                                          6.9-7.9(18H, m),                                                              8.33(1H, d, J=7.2Hz)                                         138  66  121-123 0.88(3H, d, J=7Hz), 1.1-3.1(10H, m)                                           3.49(3H, s), 4.20(2H, m),                                                     6.54(1H, d, J=7Hz),                                                           7.12(2H, d, J=7Hz), 7.48(5H, m),                                              7.74(2H, d, J=7Hz),                                                           8.26(1H, d, J=7Hz)                                           146  93   98-102 0.85(3H, t, J=7Hz), 1.0-3.2(15H, m)                                           3.47(3H, s), 4.26(2H, m),                                                     6.58(1H, d, J=7Hz),                                                           7.10(2H, d, J=7Hz), 7.48(5H, m),                                              7.72(2H, d, J=7Hz),                                                           8.18(1H, d, J=7Hz)                                           147-1                                                                              44   98-100 0.85(6H, d, J=7Hz), 1.0-3.2(11H, m)                                           3.48(3H, s), 4.37(2H, m),                                                     6.50(1H, d, J=7Hz),                                                           7.10(2H, d, J=7Hz), 7.48(5H, m),                                              7.74(2H, d, J=7Hz),                                                           8.24(1H, d, J=7Hz)                                           154  68  52-55   1.16(3H, d, J=7Hz), 1.60(5H, m),                                              2.34(3H, s), 2.5-3.3(2H, m),                                                  3.50(3H, s), 4.18(1H, m),                                                     4.52(1H, m), 6.50(1H, d, J=7Hz),                                              7.12(2H, d, J=7Hz), 7.48(5H, m),                                              7.76(2H, d, J=7Hz)                                                            8.28(1H, d, J=7Hz)                                           171-3                                                                              81  128-129 1.3-2.2(4H, m), 2.33(3H, s),                                                  2.40(3H, s), 2.5-3.4(3H, m),                                                  3.52(3H, s),                                                                  4.58(2H, br. d, J=12.6Hz),                                                    6.48(1H, d, J=7.2Hz),                                                         7.0-7.9(13H, m),                                                              8.28(1H, d, J=7.2Hz),                                                         13.0-15.0(1H, m)                                            2004  64  167-169 0.89(6H, d, J=7Hz), 1.3-2.7(9H, m),                                           3.50(3H, s), 4.26(2H, m),                                                     6.52(1H, d, J=7Hz),                                                           7.12(2H, d, J=7Hz), 7.48(5H, m),                                              7.76(2H, d, J=7Hz),                                                           8.28(1H, d, J=7Hz)                                          2012  83  186-187 1.4-2.2(4H, m), 2.33(3H, s),                                                  2.44(3H, s), 2.5-3.4(3H, m),                                                  3.55(3H, s),                                                                  4.65(2H, br. d, J=12.6Hz),                                                    7.0-7.5(11H, m), 7.70(4H, m),                                                 8.35(1H, d, J=7.2Hz)                                        2020  100 54-60   1.7-2.2(4H, m), 2.34(3H, s),                                                  2.5-3.3(3H, m), 3.4-3.7(2H, m),                                               3.55(3H, s), 6.9-7.9(17H, m),                                                 8.35(1H, m)                                                 2028  100 60-70   2.4-3.1(4H, m), 2.35(3H, s),                                                  2.5-3.2(3H, m), 3.50(3H, s),                                                  4.24(2H, br. d, J=12.6Hz),                                                    7.0-7.5(12H, m), 7.75(2H, m),                                                 8.04(2H, m)                                                 2036  100 54-58   1.4-2.1(8H, m), 2.32(6H, m),                                                  2.2-3.3(6H, m), 3.55(3H, s),                                                  4.50(4H, m), 6.95-7.8(23H, m),                                                9.1(2H, m)                                                  2044  100 62-72   1.4-2.2(4H, m), 2.35(3H, s),                                                  2.5-3.4(3H, m), 3.59(3H, s),                                                  4.36(2H, br. d, J=12.6Hz),                                                    6.48(1H, dd. J=3.6, 2.0Hz),                                                   7.0-7.6(9H, m),                                                               7.76(2H, d, J=7.2Hz), 7.97(1H, s),                                            8.15(1H, s), 10.92(1H, m)                                   2116  78  138-140 0.96(6H, s), 1.36(4H, m),                                                     2.33(3H, s), 3.48(3H, s),                                                     3.60(4H, m), 6.50(1H, d, J=7Hz),                                              7.12(2H, d, J=7Hz), 7.48(5H, m),                                              7.74(2H, d, J=7Hz),                                                           8.24(1H, d, J=7Hz)                                          2124  61  145-147 0.91(3H, t, J=7Hz), 1.60(2H, m),                                              2.34(3H, s), 2.7-4.0(9H, m),                                                  6.54(1H, d, J=7Hz), 7.0-7.6(12H, m)                                           7.76(2H, d, J=7Hz),                                                           8.37(1H, d, J=7Hz)                                          2132  61  175-178 1.4-2.2(4H, m), 2.32(3H, s),                                                  2.6-3.4(3H, m), 3.59(3H, s),                                                  4.68(2H, br. d, J=12.6Hz),                                                    6.63(1H, d, J=7.2Hz)                                                          7.0-7.4(8H, m), 7.45-7.90(4H, m),                                             8.28(1H, d, J=7.2Hz), 12-14(1H, m)                          2140  100 82-88   1.1-2.0(4H, m), 2.31(6H, s),                                                  2.4-3.2(3H, m), 3.5(3H, s),                                                   4.18(2H, br. d, J=12.6Hz),                                                    6.81(1H, d, J=7.2Hz),                                                         6.9-7.4(9H, m), 7.55-8.0(5H, m),                                              8.2-8.6(2H, m),                                                               8.85(1H, d, J=5.2Hz), 9.10(1H, s),                                            9.62(2H, m)                                                 2174  62   94-100 1.2-3.3(10H, m), 3.47(3H, s),                                                 4.34(2H, m), 6.55(1H, d, J=7Hz),                                              6.9-7.9(14H, m), 8.08(1H, d, J=7Hz)                         2182  78  >300    1.5-2.1(4H, m), 2.32(3H, s),                                                  2.4-3.2(2H, m), 3.48(3H, s),                                                  4.07-4.7(3H, m), 6.46(1H, d, J=7Hz)                                           6.72(2H, d, J=7Hz), 7.18(7H, m),                                              7.48(2H, d, J=7Hz),                                                           7.68(2H, d, J=7Hz),                                                           7.88(1H, d, J=7Hz)                                          2188  60  151-156 1.4-3.2(10H, m), 3.41(3H, s),                                                 4.40(2H, m), 6.50(1H, d, J=7Hz),                                              7.08(2H, d, J=7Hz), 7.42(5H, m),                                              7.66(2H, d, J=7Hz),                                                           7.88(1H, d, J=7hz)                                          2194  39  106-109 1.4-3.3(10H, m), 3.45(3H, s),                                                 4.52(2H, m), 6.50(1H, d, J=7Hz),                                              7.0-8.1(19H, m)                                             2202  52  203-207 1.5-3.4(10H, m), 3.46(3H, s),                                                 4.44(2H, m), 6.60(1H, d, J=7Hz),                                              7.10(2H, d, J=7Hz), 7.2-7.9(13H, m)                         2210  100 62-66   1.3-2.2(10H, m), 2.31(3H, s),                                                 2.5-3.6(7H, m), 3.25(3H, s),                                                  4.72(2H, br. d, J=12.6Hz),                                                    6.10(1H, d, J=7.2Hz),                                                         7.0- 7.4(7H, m),                                                              7.75(2H, d, J=7.2Hz),                                                         8.16(1H, d, J=7.2Hz)                                        2218  89  186-187 1.4-2.2(4H, m), 2.31(3H, s),                                                  2.6-3.4(3H, m), 3.49(3H, s),                                                  4.63(2H, br. d, J=12.6Hz),                                                    6.76(1H, d, J=7.2Hz),                                                         6.9-7.8(14H, m),                                                              7.95(1H, d, J=7.2Hz), 10.20(1H, s)                          2234  94   95-102 1.45-2.15(4H, m), 2.32(6H, s),                                                2.5-3.2(3H, m), 2.80(3H, s),                                                  3.23(3H, s), 3.35(4H, m),                                                     3.80(4H, m),                                                                  4.60(2H, br. d, J=12.6Hz),                                                    6.62(1H, d, J=7.2Hz),                                                         6.96-7.45(9H, m),                                                             7.76(4H, d, J=7.2Hz),                                                         8.23(1H, d, J=7.2Hz)                                        2242  76  116-117 1.40(3H, t, J=7.2Hz),                                                         1.4-2.2(4H, m), 2.34(3H, s),                                                  2.6-3.5(3H, m), 3.48(3H, s),                                                  4.35(2H, q, J=7.2Hz),                                                         4.76(2H, br. d, J=12.6Hz),                                                    7.0-7.4(7H, m),                                                               7.6(1H, d, J=7.2Hz),                                                          7.78(2H, d, J=7.2Hz),                                                         8.35(1H, d, J=7.2Hz),                                                         14.0(1H, m)                                                 2250  30  192-196 1.50-3.40(10H, m), 3.50(5H, s),                                               4.05(2H, s), 4.70(2H, m),                                                     7.10(2H, d, J=7Hz), 7.23(10H, m),                                             7.48(1H, d, J=7Hz),                                                           7.76(2H, d, J=7Hz),                                                           8.35(1H, d, J=7Hz)                                          2260  45  166-173 0.85(3H, t, J=7Hz), 1.1-2.2(8H, m),                                           2.33(3H, s), 2.82(4H, m),                                                     3.46(3H, s), 5.10(1H, m),                                                     6.28(1H, d, J=7Hz),                                                           7.10(2H, d, J=7Hz), 7.36(5H, m),                                              7.66(2H, d, J=7Hz),                                                           7.96(1H, d, J=7Hz), 8.76(2H, m)                             2270  50  168-169 1.52(4H, m), 2.30(3H, s),                                                     2.4-3.2(3H, m), 3.42(3H, s),                                                  4.40(2H, m), 6.46(1H, d, J=7Hz),                                              7.04(2H, d, J=7Hz), 7.36(15H, m),                                             7.66(2H, d, J=7Hz),                                                           8.21(1H, d, J=7Hz)                                          2278  86  163-164 1.4-2.2(4H, m), 2.35(3H, s),                                                  2.5-3.4(6H, m), 4.5-5.0(4H, m),                                               6.10(1H, d, J=7.2Hz),                                                         7.0-7.5(12H, m),                                                              7.80(2H, d, J=7.2Hz), 8.15(1H, m),                                            13.15(1H, m)                                                2286  90  204-207 1.4- 2.15(4H, m), 2.33(3H, s),                                        (Decomp.)                                                                             2.5-3.3(3H, m), 3.48(3H, s),                                                  4.70(2H, br. d, J=12.6Hz),                                                    5.05(2H, s), 6.7-7.5(13H, m),                                                 7.68(2H, m), 8.35(1H, m)                                    2294  100 48-52   1.4-2.15(4H, m), 2.32(3H, s),                                                 2.6-3.2(3H, m), 3.0(6H, s),                                                   3.26(3H, s),                                                                  4.73(2H, br. d, J=12.6Hz),                                                    6.10(1H, d, J=7.2Hz),                                                         7.0-7.4(7H, m),                                                               7.76(2H, d, J=7.2Hz),                                                         8.18(1H, d, J=7.2Hz)                                        2302  71  50-55   1.21(6H, t, J=7.2Hz),                                                         1.5-2.2(4H, m), 2.32(3H, s),                                                  2.5-3.7(10H, m),                                                              4.70(2H, br. d, J=12.6Hz),                                                    6.08(1H, m), 6.9-7.5(7H, m),                                                  7.76(2H, d, J=7.2Hz), 8.18(1H, m),                                            13.33(1H, m)                                                2310  60  174-176 1.88(4H, m), 2.32(3H, s),                                                     3.40(3H, m), 3.51(3H, s),                                                     4.32(2H, m), 6.60(1H, d, J=7Hz),                                              7.10(2H, d, J=7Hz),                                                           7.40(2H, d, J=7Hz), 7.50(5H, m),                                              7.74(2H, d, J=7Hz),                                                           7.84(2H, d, J=7Hz),                                                           8.24(1H, d, J=7Hz)                                          2318  67  80-85   1.4-2.1(4H, m), 2.6-3.4(3H, m),                                               3.92(3H, s), 7.0(1H, d, J=7Hz),                                               7.18(2H, d, J=7Hz), 7.1-7.8(10H, m)                                           7.78(2H, d, J=7Hz),                                                           8.50(2H, d, J=7Hz)                                          2322  92  192-194 1.4-2.2(4H, m), 2.32(3H, s),                                                  2.5-3.4(3H, m), 3.29(3H, s),                                                  3.58(8H, m),                                                                  4.69(2H, br. d, J=12.6Hz),                                                    6.20(1H, d, J=7.2Hz),                                                         6.95-7.42(7H, m),                                                             7.74(2H, d, J=7.2Hz),                                                         8.23(1H, d, J=7.2Hz)                                        2330  78  160-162 1.4-2.2(4H, m), 2.32(3H, s),                                                  2.6-3.6(3H, m), 3.69(3H, s),                                                  4.79(2H, br. d, J=12.6Hz),                                                    7.0-7.9(15H, m),                                                              8.40(1H, d, J=7.2Hz)                                         154-2                                                                              86  191-193 1.4-2.2(4H, m), 2.32(3H, s),                                                  2.5-3.4(3H, m), 3.44(3H, s),                                                  3.47(3H, s), 4.4(2H, s),                                                      4.70(2H, br. d, J=12.6Hz),                                                    7.0-7.4(6H, m),                                                               7.75(2H, d, J=7.2Hz),                                                         8.40(1H, d, J=7.2Hz)                                         171-5                                                                              74  172-173 1.41(3H, t, J=7.2Hz),                                                         1.4-2.2(4H, m), 2.32(3H, s),                                                  2.5-3.4(3H, m), 3.52(3H, s),                                                  4.05(2H, q, J=7.2Hz),                                                         4.60(2H, br. d, J=12.6Hz),                                                    6.40(1H, d, J=7.2Hz),                                                         6.89(2H, d, J=7.2Hz),                                                         7.0-7.5(7H, m),                                                               7.56(2H, d, J=7.2Hz),                                                         7.75(2H, d, J=7.2Hz),                                                         8.22(1H, d, J=7.2Hz)                                         298  70  217-218 1.6-2.2(4H, m), 2.35(3H, s),                                                  2.7-3.5(3H, m), 4.90(2H, m),                                                  7.22(8H, m), 7.88(6H, m),                                                     8.75(1H, d, J=7Hz)                                           306  70  108-110 1.88(4H, m), 2.31(3H, s),                                                     3.42(3H, m), 3.51(3H, s),                                                     4.30(2H, m), 6.58(1H, d, J=7Hz),                                              7.10(2H, d, J=7Hz), 7.50(8H, m),                                              7.72(2H, d, J=7Hz), 7.88(2H, m),                                              8.24(1H, d, J=7Hz)                                           242  93  119-122 1.3-2.2(4H, m), 2.33(3H, s),                                                  2.5-3.4(3H, m), 3.52(3H, s),                                                  4.55(2H, br. d, J=12.6Hz),                                                    6.59(1H, d, J=7.2Hz),                                                         7.0-7.5(9H, m), 7.5- 8.0(4H, m),                                              8.35(1H, d, J=7.2Hz)                                        2022-1                                                                              46  118-121 1.75-2.90(4H, m), 2.35(3H, s),                                                2.95-3.40(3H, m), 3.55(3H, s),                                                3.68(2H, br. d, J=12.6Hz),                                                    6.9-8.0(16H, m), 8.70(1H, br. s)                            2023-1                                                                              100 57-64   1.8-3.0(4H, m), 2.38(3H, s),                                                  3.1-4.0(5H, m), 3,59(3H, s),                                                  6.70-8.0(15H, m)                                             150  100 48-58   0.5-1.8(5H, m),                                                               0.87(3H, d, J=5.2Hz), 2.35(3H, s),                                            2.4-3.2(2H, m), 3.4-4.5(2H, m),                                               6.22(1H, d, J=7.2Hz),                                                         7.0-7.9(14H, m),                                                              8.28(1H, d, J=7.2Hz)                                         171-9                                                                              88  137-139 1.2-2.2(4H, m), 2.32(3H, s),                                                  2,5-3.4(3H, m), 3.51(3H, s),                                                  4.44(2H, br. d, J=12.6Hz),                                                    6.84(1H, d, J=7.2Hz),                                                         6.9-7.9(14H, m),                                                              8.40(1H, d, J=7.2Hz)                                         170-11                                                                             100 75-80   1.3-2.2(4H, m), 2.32(3H, s),                                                  2.5-3.5(3H, m), 3.45(3H, s),                                                  4.48(2H, br. d, J=12.6Hz),                                                    6.95-7.5(11H, m),                                                             7.72(2H, d, J=7.2Hz),                                                         8.44(1H, d, J=7.2Hz)                                        170-2 88  147-148 1.4-2.1(4H, m), 2.33(3H, s),                                                  2.5-3.5(3H, m), 3.55(3H, s),                                                  4.72(2H, br. d, J=12.6Hz),                                                    6.8-8.0(17H, m),                                                              8.40(1H, d, J=7.2Hz)                                         171-7                                                                              95  70-76   1.3-2.1(4H, m), 2.32(3H, s),                                                  2.36(3H, s), 2.5-3.3(3H, m),                                                  3.44(3H, s),                                                                  4.56(2H, br. d, J=12.6Hz),                                                    6.80(1H, d, J=7.2Hz),                                                         9.0-9.6(11H, m),                                                              7.73(2H, d, J=7.2Hz),                                                         8.30(1H, d, J=7.2Hz)                                         171-13                                                                             97  154-158 1.2-2.1(4H, m), 2.3(3H, s),                                                   2.5-3.3(3H, m), 3.48(3H, s),                                                  4.4(2H, br. d, J=12.6Hz),                                                     6.7(1H, d, J=7.2Hz),                                                          7.0-7.9(12H, m),                                                              8.39(1H, d, J=7.2Hz)                                        __________________________________________________________________________

EXAMPLE 3 4-(N-methylbenzamino)-2-(4-phenylpiperidino)pyrimidinehydrochloride ((compound No. 170)

A solution of 0.27 g (0.0027 mole) of concentrated hydrochloric acid in2 ml of CH₃ OH was slowly added to a solution of 1.0 g (0.0027 mole) of4-(N-methylbenzamino)-2-(4-phenylpiperidino)pyrimidine in 10 ml ofchloroform. After the addition, the mixture was concentrated underreduced pressure to give 1.1 g (yield 100%) of the desired product.

Melting point: 80°-84° C.

¹ H-NMR spectrum (deuterochloroform, δppm) 1.4-22(4H, m), 2.6-3.4(3H,m), 3.56(3H, s), 2.2(2H, m), 6.69(1H, d, J=7.2 Hz), 7.0-7.7(10H, m),8.1(1H, d, J=7.2 Hz).

In the same way as above, the following compounds were produced, andtheir data are given in Table 5.

                  TABLE 5                                                         ______________________________________                                        Com-          Melting                                                         pound Yield   point    .sup.1 H-NMR spectrum                                  No.   (%)     (°C.)                                                                           (CDCl.sub.3 solution, δ ppm)                     ______________________________________                                         662  46      241-243  10.9(1H, br), 8.03(1H, d, J = 5Hz),                                           7.2-7.8(10H, m),                                                              6.28(1H, d, J = 5Hz), 4.63(2H, s),                                            3.50(3H, s), 3.0-3.4(1H, m),                                                  1.48(6H, d, J = 7Hz)                                   2052  86      96-99    12.9(2H, br), 8.03(1H, d, J = 5Hz),                                           7.2-7.6(5H, m),                                                               6.36(1H, d, J = 5Hz),                                                         4.5-4.8(2H, m), 3.56(3H, s),                                                  1.1-3.3(17H, m)                                        2060  93      185-189  7.98(1H, d, J = 7Hz),                                                         7.3-7.7(5H, m),                                                               6.64(1H, d, J = 7Hz),                                                         3.6-4.4(6H, m), 3.62(3H, s),                                                  1.4-2.2(4H, m)                                         2070  93      77-80    8.03(1H, d, J = 5Hz),                                                         7.2-7.6(5H, m),                                                               6.36(1H, d, J = 5Hz),                                                         4.0-4.7(2H, m), 3.63(3H, s),                                                  1.0-4.0(12H, m)                                        2076  86      237-239  12.5(1H, br),                                                                 8.53(1H, d, J = 5Hz),                                                         8.12(9H, d, J = 7Hz),                                                         7.32(2H, d, J = 7Hz),                                                         6.43(1H, d, J = 5Hz),                                                         7.2-7.7(5H, m), 4.8-5.0(2H, m),                                               3.53(3H, s), 1.1-3.4(7H, m)                            2084  90      60-63    12.3(1H, br),                                                                 8.70(1H, d, J = 7Hz),                                                         7.2-7.6(5H, m),                                                               6.37(1H, d, J = 7Hz),                                                         4.0-4.8(2H, m), 2.63(3H, s),                                                  0.8-3.5(14H, m)                                        2092  86      183-186  8.06(1H, d, J = 7Hz),                                                         7.2-7.6(5H, m),                                                               6.38(1H, d, J = 7Hz), 3.60(3H, s),                                            3.10(3H, s), 1.8-4.0(10H, m)                           2100  90      213-215  8.70(1H, d, J = 5Hz),                                                         7.3-7.6(5H, m),                                                               6.48(1H, d, J = 5Hz),                                                         4.4-4.8(2H, m),                                                               4.20(2H, q, J = 7Hz), 3.58(3H, s),                                            1.32(3H, t, J = 7Hz),                                                         1.5-3.4(7H, m)                                         2108  93      89-91    10.5(1H, br), 8.07(1H, d, J = 5Hz),                                           7.0-7.6(15H, m),                                                              6.18(1H, d, J = 5Hz), 4.68(4H, s),                                            3.44(3H, s)                                            2148  94      218-221  8.05(1H, d, J = 7Hz),                                                         7.2-7.5(5H, m),                                                               6.40(1H, d, J = 7Hz),                                                         4.3-4.5(2H, m), 2.3-4.0(7H, m),                                               3.30(5.6H), 3.58(3H, s)                                2156  89      57-60    14.0(1H, br), 8.04(1H, d, J = 7Hz),                                           7.3-7.6(5H, m),                                                               6.56(1H, d, J = 7Hz),                                                         3.50(3H, s), 4.0-4.8(2H, m),                                                  1.0-2.4(14H, m)                                        2164  96      140-142  8.03(1H, d, J = 5Hz),                                                         7.2-7.6(5H, m),                                                               6.40(1H, d, J = 5Hz),                                                         4.2-4.5(2H, m), 3.63(3H, s),                                                  1.0-3.8(10H, m)                                        2226  86      187-189  7.9-8.1(3H, m), 7.2-7.7(8H, m),                                               6.66(1H, d, J = 7Hz),                                                         5.1-5.4(1H, m),                                                               3.6-4.3(4H, m), 3.55(3H, s),                                                  1.7-2.2(4H, m)                                         2342  94      135-138  12.0-12.8(1H, br),                                                            8.03(1H, d, J = 7Hz),                                                         7.2-7.6(5H, m),                                                               6.50(1H, d, J = 7Hz), 3.53(3H, s),                                            1.0-3.7(13H, m)                                        2350  88      153-157  12.8(1H, br), 8.03(1H, d, J = 7Hz),                                           7.2-7.9(10H, m),                                                              6.60(1H, d, J = 7Hz),                                                         4.3-4.6(2H, m), 3.50(3H, s),                                                  1.5-4.0(7H, m)                                         307-1 94      259-261  8.07(1H, d, J = 7Hz),                                                         7.2-7.6(5H, m),                                                               6.38(1H, d, J = 7Hz),                                                         4.2-4.4(2H, m), 3.50(3H, s),                                                  1.4-4.0(10H, m)                                        ______________________________________                                    

The following compounds were obtained by the same method as in Example 3except that sulfuric acid, phosphoric acid, etc. were used instead ofhydrochloric acid.

                  TABLE 6                                                         ______________________________________                                        Com-          Melting                                                         pound Yield   point    .sup.1 H-NMR spectrum                                  No.   (%)     (°C.)                                                                           (CDCl.sub.3 solution, δ ppm)                     ______________________________________                                        165   84      151-154  1.0-2.0(4H, m), 2.5-3.2(3H, m),                                               3.45(3H, s),                                                                  4.24(2H, br. d, J=12.6Hz),                                                    6.67(1H, d, J=7.2Hz),                                                         6.73(1H, d, J=7.2Hz),                                                         7.0-7.6(10H, m),                                                              8.15(1H, d, J=7.2Hz)                                   166   67      108-113  1.2-2.0(4H, m), 2.5-3.0(3H, m),                                               3.51(3H, s),                                                                  4.58(2H, br. d, J=12.6Hz),                                                    6.15(1H, d, J=5.4Hz),                                                         7.0-7.55(10H, m),                                                             8.02(1H, d, J=5.4Hz),                                                         11.0(1H, m)                                            167   37      94-96    1.3-2.2(4H, m), 2.6-3.2(3H, m),                                               3.52(3H, s),                                                                  4.54(2H, br. d, J=12.6Hz),                                                    6.32(2H, s), 6.49(1H, d, J=7.2Hz),                                            7.0-7.7(10H, m),                                                              8.15(1H, d, J=7.2Hz),                                                         8.93(2H, br. s)                                        169   32      132-136  1.3-2.2(4H, m), 2.55-3.3(3H, m),                                              3.49(3H, s),                                                                  4.49(2H, br. d, J=12-6Hz),                                                    6.58(1H, d, J=7.2Hz),                                                         6.8-8.5(19H, m)                                        171   45      108-112  1.0-1.9(4H, m), 2.4-2.9(6H, m),                                               3.0-3.6(3H, m), 3.40(3H, s),                                                  4.36(2H, br. d, J=12.6Hz),                                                    6.42(1H, d, J=5.4Hz),                                                         7.0-7.4(5H, m), 7.35(5H, s),                                                  8.15(1H, d, J=5.4Hz),                                                         12-13(2H, m)                                           171-1 49      133-135  1.0-1.8(4H, m), 2.4-1.9(3H, m),                                               3.0-3.5(3H, m), 3.40(3H, s),                                                  4.30(2H, s),                                                                  4.38(2H, br. d, J=12.6Hz),                                                    6.42(1H, d, J=5.4Hz,                                                          7.0-7.4(5H, m), 7.35(5H, s),                                                  8.15(1H, d, J=5.4Hz),                                                         12-13(1H, m)                                           171-1-1                                                                             90      124-127  1.2-2.0(4H, m), 2.5-3.0(3H, m),                                               3.48(3H, s),                                                                  4.55(2H, br. d, J=12.6Hz),                                                    6.17(1H, d, J=5.4Hz),                                                         6.69(2H, s), 6.9-7.5(10H, m),                                                 8.02(1H, d, J=5.4Hz)                                   ______________________________________                                    

EXAMPLE 4 Production of2-isopropylamino-4-methyl-5-methoxycarbonylpyrimidine (compound No. 800)

18.2 g (0.12 mole) of 1-amidinoisopropylamine sulfate was added to asolution of 13.0 g (0.12 mole) of potassium t-butoxide in 200 ml ofmethanol, and the mixture was stirred at room temperature for 30minutes. Then, 18.5 g (0.12 mole) of ethyl2-methoxymethyleneacetoacetate was added at 0° C. over 30 minutes, andthe mixture was stirred for 3 hours. The solvent was evaporated, and theresidue was extracted with ether and purified by silica gel columnchromatography to give 10.6 g (yield 44%) of the desired product as ayellow solid.

Melting point: 118°-119° C.

¹ H-NMR spectrum (deuterochloroform, δppm) 1.26(6H, d, J=7 Hz), 2.66(3H,s), 3.87(3H, s), 4.25(1H, sex, J=7 Hz), 5.40(1H, br. s), 8.80(1H, s).

EXAMPLE 5 Production of2-piperidino-4-methoxymethyl-5-methoxycarbonylpyrimidine (compound No.820)

Sodium hydride (0.19 g; 7.8 mmoles) was added to 50 ml of methanol, and2.1 g (7.8 mmoles) of2-piperidino-4-chloromethyl-5-methoxycarbonylpyrimidine was added atroom temperature. The mixture was stirred for 3 hours. After the solventwas evaporated, water was added to the residue and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography to give 0.90 g (yield44%) of the desired product as a white solid.

Melting point: 89°-92° C.

¹ H-NMR spectrum (deuterochloroform, δppm): 1.70(6H, m), 3.54(3H, s),3.86(3H, s), 3.92(4H, m), 4.83(2H, s), 8.82(1H, s).

In the same way as above, the following compounds were obtained.

                  TABLE 7                                                         ______________________________________                                        Com-           Melting                                                        pound Yield    point    .sup.1 H-NMR spectrum                                 No.   (%)      (°C.)                                                                           (CDCl.sub.3 solution, δ ppm)                    ______________________________________                                        808   53       Oil      1.35(3H, t, J=7Hz), 1.66(6H, m),                                              2.44(3H, s), 3.90(2H, s),                                                     3.92(4H, m), 4.30(2H, q, J=7Hz),                                              8.80(1H, s)                                           816   35       Oil      1.40(3H, t, J=7Hz), 1.70(6H, m),                                              2.21(3H, s), 3.92(4H, m),                                                     4.06(2H, s), 4.36(2H, q, J=7Hz),                                              8.91(1H, s)                                           824   90       Oil      1.22(6H, d, J=8Hz),                                                           1.33(3H, t, J=8Hz), 2.36(6H, s),                                              3.84(2H, s), 5.5(1H, br, s),                                                  8.78(1H, s)                                           ______________________________________                                    

EXAMPLE 6 Production of2-isopropylamino-4-methyl-5-methoxycarbonylpyrimidine maleate (compoundNo. 804)

2.48 g (11.9 mmoles) of2-isopropylamino-4-methyl-5-methoxycarbonylpyrimidine and 1.38 g (11.9mmoles) of maleic acid were dissolved in a mixture of 20 ml of ethanoland 20 ml of chloroform, and the solution was stirred for 3 hours. Thesolvents were evaporated, and ether was added for crystallization at 0°C. The desired product was obtained in an amount of 3.21 g (yield 83%)as pale yellow crystals.

Melting point: 75°-79° C.

¹ H-NMR spectrum (deuterochloroform, δppm): 1.33(6H, d, J=7 Hz),2.85(3H, s), 3.95(3H, s), 4.36(1H, sex, J=7 Hz), 6.40(2H, s), 9.08(1H,br, s).

In the same way as above, the following compounds were produced.

                  TABLE 8                                                         ______________________________________                                        Com-             Melting                                                      pound    Yield   point      .sup.1 H-NMR spectrum                             No.      (%)     (°C.)                                                                             (CDCl.sub.3 solution, δ ppm)                ______________________________________                                        812      74      115.5-118.5                                                                              1.40(3H, t, J=7Hz),                                                           1.68(6H, m),                                                                  3.08(3H, s), 3.92(4H, m),                                                     4.34(2H, q, J=7Hz),                                                           4.72(2H, s),                                                                  6.32(2H, s), 8.90(1H, s)                          828      67      111-121    1.30(6H, d, J=8Hz),                                                           1.40(3H, t, J=8Hz),                                                           3.07(6H, s),                                                                  4.34(2H, q, J=8Hz),                                                           4.66(2H, s), 6.32(2H, s),                                                     8.92(1H, s)                                       ______________________________________                                    

EXAMPLE 7 Production of2-(4-diphenylmethylpiperazino)-5,6-dihydro-7-methyl-6-oxo(7H)pyrrolo2,3-d]pyrimidine(compound No. 3124)

1.9 g (7.5 mmoles) of 1-diphenylmethylpiperazine and 1.7 g (7.5 mmoles)of ethyl (2-methylthio-4-hydroxypyrimidin-5-yl)acetate were added to 60ml of n-amyl alcohol, and the mixture was stirred at 170° C. for 20hours. The solvent was then evaporated under reduced pressure. Tenmilliliters of phosphorus oxychloride was added to the residue, andreacted at 100° C. for 2 hours. After the reaction, the mixture wasgradually added to an aqueous solution of potassium carbonate, andextracted with methylene chloride. The organic layer was dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue, 15 ml of ethanol and a 40 % methanolsolution of methylamine was put in a pressure vessel, and reacted at140° C. for 10 hours. Then, the solvent was evaporated, and the residuewas purified by silica gel column chromatography to give 0.9 g (yield 30%) of the desired product.

Melting point: 75°-80° C.

¹ H-NMR spectrum (CDCl₃ solution, δppm): 2.43(4H, m), 3.13(3H, s),3.37(2H, s), 3.80(4H, m), 4.23(1H, s), 7.08-7.52(10H, m), 7.82(1H, s).

The following compounds were produced in the same way as above, andtheir data are shown in Table 9.

                  TABLE 9                                                         ______________________________________                                        Com-           Melting                                                        pound Yield    point     .sup.1 H-NMR spectrum                                No.   (%)      (°C.)                                                                            (CDCl.sub.3 solution, δ ppm)                   ______________________________________                                        3100  78       210-213   2.47(4H, m), 3.17(3H, s),                                                     3.39(2H, s), 3.50(2H, s),                                                     3.82(4H, m), 7.28(4H, m),                                                     7.88(1H, s)                                          3108  56       82-86     0.74(3H, d, J=7Hz),                                                           1.02(3H, d, J=7Hz), 2.38(4H, m),                                              3.13(3H, s), 3.35(2H, s),                                                     3.74(4H, m), 4.10(1H, m),                                                     7.20(5H, m), 7.80(1H, s)                             3132  38       80-85     2.42(4H, m), 3.15(3H, s),                                                     3.38(2H, s), 3.81(4H, m),                                                     4.24(1H, s), 6.8-7.5(9H, m),                                                  7.85(1H, s)                                          3140  54       105-110   2.43(4H, m), 3.15(3H, s),                                                     3.39(2H, s), 3.82(4H, m),                                                     4.24(1H, s), 7.32(9H, m),                                                     7.88(1H, s)                                          3148  35       --        2.29(3H, s), 2.43(4H, m),                                                     3.14(3H, s), 3.38(2H, s),                                                     3.80(4H, m), 4.21(1H, s),                                                     6.9-7.5(9H, m), 7.84(1H, s)                          3172  26       --        2.41(4H, m), 3.14(3H, s),                                                     3.36(2H, s), 3.80(4H, m),                                                     4.22(1H, s), 7.28(8H, m),                                                     7.84(1H, s)                                          3180  12       91-94     2.40(4H, m), 3.14(3H, s),                                                     3.37(2H, s), 3.80(4H, m),                                                     4.23(1H, s), 6.8-7.4(8H, m),                                                  7.83(1H, s)                                          3188  44       170-175   2.50(4H, m), 3.16(3H, s),                                                     3.40(2H, s), 3.84(4H, m),                                                     4.44(1H, s), 7.1-7.6(8H, m),                                                  7.84(1H, s), 8.49(1H, m)                             3196  51       179-181   2.66(4H, m), 3.12(3H, s),                                                     3.36(2H, s), 3.76(4H, m),                                                     4.88(1H, s), 7.28(4H, m),                                                     7.70(4H, m), 7.84(1H, s)                             3300  49       263-267   2.36(4H, m), 3.13(3H, s),                                           (decomp.) 3.36(2H, s), 3.92(4H, m),                                                     7.1-7.6(15H, m), 7.82(1H, s)                         3400  40                 2.78(3H, s), 3.18(3H, s),                                                     3.26(4H, m), 3.40(2H, s),                                                     3.94(4H, m), 7.87(1H, s)                             3408  68                 1.1-2.0(12H, m), 3.18(3H, s),                                                 3.32(4H, m), 4.20(2H, m),                                                     7.84(1H, s)                                          3416  61                 1.2-2.4(12H, m), 3.18(3H, s),                                                 3.3-3.8(4H, m), 7.86(1H, s)                          ______________________________________                                    

EXAMPLE 8 Production of2-(4-diphenylmethylpiperazino)-5,6-dihydro-7-methyl-6-oxo(7H)pyrrolo2,3-d]pyrimidinehydrochloride (compound No. 3128)

Concentrated hydrochloric acid (0.23 g; 2.2 mmoles) was added to anethanol/methylene chloride solution of2-(4-diphenylmethylpiperazino)-5,6-dihydro-7-methyl-6 and the solutionwas stirred at room temperature for 1 hour. The solvent was thenevaporated under reduced pressure. The residue was washed with ether togive 0.88 g (yield 90 %).

Melting point: 217°-222° C.

¹ H-NMR spectrum (CDCl₃, δppm): 3.18(3H, s), 3.20(4H, m), 3.52(2H, s),4.40(4H, m), 5.20(1H, s), 7.2-7.9 (1H, m).

In the same way as above, the following compounds were produced, andtheir data are shown in Table 10.

                  TABLE 10                                                        ______________________________________                                        Com-           Melting                                                        pound  Yield   point      .sup.1 H-NMR spectrum                               No.    (%)     (°C.)                                                                             (CDCl.sub.3 solution, δ ppm)                  ______________________________________                                        3104   82      >300       (CDCl.sub.3 --CD.sub.3 OD)                                                    3.20(3H, s), 3.30(4H, m),                                                     3.48(2H, s), 4.32(2H, s),                                                     4.54(4H, m), 7.52(4H, m),                                                     7.93(1H, s)                                         3136   80      238-243    (CDCl.sub.3 --CD.sub.3 OD)                                         (decomp.)  3.20(3H, s), 3.24(4H, m),                                                     3.50(2H, s), 3.8-4.6(4H, m),                                                  5.10(1H, s), 7.0-8.0(10H, m)                        3144   93      238-245    3.20(3H, s), 3.29(4H, m),                                          (decomp.)  3.57(2H, s), 4.58(4H, m),                                                     5.26(1H, s), 7.40(5H, m),                                                     7.90(5H, m)                                         3200   73      244-245    3.12(3H, s), 3.14(4H, m),                                          (decomp.)  3.40(2H, s), 4.56(4H, m),                                                     5.45(1H, s), 7.17-8.27(9H, m)                       3412   70      250-252    1.2-2.2(12H, m), 3.26(3H, s),                                      (decomp.)  3.52(4H, m), 4.50(2H, m),                                                     8.00(1H, s)                                         3420   70      256-257    1.2-2.5(12H, m), 3.25(3H, s),                                      (decomp.)  3.3-4.2(4H, m), 7.99(1H, s)                         ______________________________________                                    

EXAMPLE 9 Production of2-(4-(α(4-methylphenyl)benzyl)piperazino)-5,6-dihydro-7-methyl-6-oxo(7H)pyrrolo[2,3-d)pyrimidinep-toluenesulfonate (compound No. 3152)

An ethyl acetate/methanol solution of 0.13 9 (0.75 mmole) ofp-toluenesulfonic acid was added to an ethyl acetate/methanol solutionof 0.31 g (0.75 mmole) of2-(4-(α(4-methylphenyl)benzyl)piperazino)-5,6-dihydro-7-methyl-6-oxo(7H)pyrrolo2,3-d)pyrimidine,and the mixture was stirred at room temperature for 1 hour. The solventswere then evaporated under reduced pressure, and the residue was washedwith hexane to give 0.36 g (yield of the desired compound.

Melting point: 150°-155° C.

¹ H-NMR spectrum (CDCl₃ solution, δppm): 2.28(3H, s), 2.34(3H, s),3.00(4H, m), 3.11(3H, s), 3.39(2H, s), 4.14(4H, m), 4.73 (1H, s),7.0-7.8(13H, m), 7.93(1H, s).

In the same way as above, the following compounds were produced, andtheir data are shown in Table 11.

                  TABLE 11                                                        ______________________________________                                        Com-          Melting                                                         pound Yield   point      .sup.1 H-NMR spectrum                                No.   (%)     (°C.)                                                                             (CDCl.sub.3 solution, δ ppm)                   ______________________________________                                        3112  92      --         0.86(3H, d, J=7Hz),                                                           1.16(3H, d, J=7Hz),                                                           2.35(3H, s),                                                                  3.12(7H, m), 3.39(2H, s),                                                     4.20(5H, m),                                                                  7.14(2H, d, J=7Hz),                                                           7.35(5H, m),                                                                  7.76(2H, d, J=7Hz),                                                           7.87(1H, s)                                          3176  90      145-150    2.34(3H, s), 2.83(4H, m),                                                     3.13(3H, s), 3.43(2H, s),                                                     4.06(4H, m), 4.72(1H, s),                                                     7.0-7.5(10H, m),                                                              7.66(2H, d, J=7Hz),                                                           8.03(1H, s)                                          3184  91      124-130    2.34(3H, s), 2.74(4H, m),                                                     3.14(3H, s), 3.43(2H, s),                                                     4.04(4H, m), 4.56(1H, s),                                                     6.8-7.8(12H, m), 8.01(1H, s)                         3192  100     135-140    2.35(3H, s), 3.0-3.4(4H, m),                                                  3.16(3H, s), 3.44(2H, s),                                                     4.18(4H, m), 5.34(1H, s),                                                     7.0-7.8(8H, m),                                                               7.11(2H, d, J=7Hz),                                                           7.74(2H, d, J=7Hz),                                                           7.96(1H, s), 8.60(1H, m)                             3404  70      220-223    (CDCl.sub.3 --CD.sub.3 OD)                                         (decomp.)  2.38(3H, s), 2.86(3H, s),                                                     3.27(3H, s), 3.38(4H, m),                                                     3.60(2H, s), 4.03(4H, m),                                                     7.16(2H, d, J=7Hz),                                                           7.64(2H, d, J=7Hz), 8.02(1H, s)                      ______________________________________                                    

EXAMPLE 1B

Tablets each containing 10 mg of an active ingredient were prepared bythe following procedure.

    ______________________________________                                                           Per tablet                                                 ______________________________________                                        Active ingredient    10 mg                                                    Corn starch          55 mg                                                    Crystalline cellulose                                                                              35 mg                                                    Polyvinyl pyrrolidone (as                                                                           5 mg                                                    10% aqueous solution)                                                         Carboxymethyl cellulose calcium                                                                    10 mg                                                    Magnesium stearate    4 mg                                                    Talc                  1 mg                                                    Total                120 mg                                                   ______________________________________                                    

The active ingredient, corn starch and crystalline cellulose were passedthrough an 80-mesh sieve and thoroughly mixed. The mixed powder wasgranulated together with the polyvinyl pyrrolidone solution, and passedthrough an 18-mesh sieve. The resulting granules were dried at 50° to60° C. and again passed through an 18-mesh sieve to adjust their sizes.The carboxymethyl cellulose calcium, magnesium stearate and talc, whichhad been passed through an 80-mesh sieve, were added to the granules.They were mixed and tableted by a tableting machine to produce tabletseach having a weight of 120 mg.

EXAMPLE 2B

Tablets each containing 200 mg of an active ingredient were produced bythe following procedure.

    ______________________________________                                                       Per tablet                                                     ______________________________________                                        Active ingredient                                                                              200 mg                                                       Corn starch       50 mg                                                       Crystalline cellulose                                                                          42 mg                                                        Silicic anhydride                                                                               7 mg                                                        Magnesium stearate                                                                              1 mg                                                        Total            300 mg                                                       ______________________________________                                    

The above components were passed through an 80-mesh sieve and thoroughlymixed. The resulting mixed powder was compression-molded to producetablets each having a weight of 300 mg.

EXAMPLE 3B

Capsules each containing 100 mg of an active ingredient were produced bythe following procedure.

    ______________________________________                                                       Per capsule                                                    ______________________________________                                        Active ingredient                                                                              100 mg                                                       Corn starch       40 mg                                                       Lactose           5 mg                                                        Magnesium stearate                                                                              5 mg                                                        Total            150 mg                                                       ______________________________________                                    

The above components were mixed, passed through an 80-mesh sieve, andthoroughly mixed. The resulting mixed powder was filled into capsules inan amount of 150 mg for each.

EXAMPLE 4B

Injectable preparations in vials each containing 5 mg of an activeingredient were produced by the following procedure.

    ______________________________________                                                       Per vial                                                       ______________________________________                                        Active ingredient                                                                               5 mg                                                        Mannitol         50 mg                                                        ______________________________________                                    

Just prior to use, these compounds were dissolved in 1 ml of distilledwater for injection, and administered.

EXAMPLE 5B

Injectable preparations in ampoules each containing 50 mg of an activeingredients were produced in accordance with the following recipe.

    ______________________________________                                                         Per ampoule                                                  ______________________________________                                        Active ingredient  50 mg                                                      Sodium chloride    18 mg                                                      Distilled water for injection                                                                    proper amount                                              Total              2 ml                                                       ______________________________________                                    

EXAMPLE 6B

An adhesive patch containing 17.5 mg of an active ingredient wasproduced by the following procedure.

Ten parts of poly(ammonium acrylate) was dissolved in 60 parts of water.Two parts of glycerin diglycidyl ether was dissolved under heat in 10parts of water. Furthermore, 10 parts of polyethylene glycol (grade400), 10 parts of water and 1 part of an active ingredient were stirredto form a solution. While the aqueous solution of poly(ammoniumacrylate) was stirred, the aqueous solution of glycerin diglycidiylether and the solution containing the active ingredient, polyethyleneglycol and water were added and mixed. The resulting solution forhydrogel was coated on a pliable plastic film so that the rate of theactive ingredient was 0.5 mg per cm² The surface was covered withreleasing paper and cut to a size of 35 cm² to form an adhesive patch.

EXAMPLE 7B

An adhesive patch containing 10 mg of an active ingredient was producedby the following procedure.

An aqueous sol is prepared from 100 parts of poly(sodium acrylate), 100parts of glycerin, 150 parts of water, 0.2 part of triepoxypropylisocyanurate, 100 parts of ethanol, 25 parts of isopropyl myristate, 25parts of propylene glycol and 15 parts of the active ingredient. The solwas then coated to a thickness of 100 micrometers on the non-wovenfabric surface of a composite film composed of a rayon non-woven fabricand a polyethylene film to form an adhesive layer containing the drug.The amount of the release aids (isopropyl myristate and propyleneglycol) contained in this layer was about 30 % by weight. The adhesivelayer was then crosslinked at 25° C. for 24 hours, and a releasing filmwas bonded to the adhesive layer surface. The entire film was then cutinto pieces each having an area of 35 cm².

The biological activities in vitro of the compounds of formula (1), (2)or (3) on cells of the nervous system were tested. The cells tested weremouse neuroblastoma cell line neuro-2a (Dainippon Pharmaceutical Co.,Ltd.), NS-20Y, etc. which have been established as the cells of thenervous system. The above nerve cells were grown in an incubator at 37°C. in the presence of 5 % carbon dioxide gas exponentially, and thencultivated for a certain period of time together with the compounds ofthe invention. The results demonstrate that the compounds of theinvention have nerve cell growth promoting activity and neuriteformation and sprouting promoting activity which are markedly higherwith a significance than a control, and are equal to, or higher than,isaxonine as a control drug (the compound described in Japanese PatentPublication No. 28548/1984).

The biological activities of the compounds of the invention on rat PC-12pheochromocytoma cell line were also tested. When NGF is added to PC-12cells, the neurites sprout. It was shown that when the compound of thisinvention is added at this time, the binding of NGF to the PC-12 cellsand the up-take of NGF into the cells increased, and that the sproutingof the neurites also increased.

When the effect of the compounds of this invention on the binding of NGFto rabbit superior cervical ganglion was examined, they were found topromote the NGF binding.

Rats having crushed sciatic nerves were prepared as a model ofperipheral nervous disorder, and the effects of the compounds of thisinvention on it were tested. It was made clear that the compounds of thepresent invention have an effect of promoting recovery of the interdigitdistance and the weight of the soleus muscle to normal values.

Rat and mouse models of central nervous disorders were prepared, and thepharmacological effects of the compounds of this invention were tested.Specifically, nigral dopamine cells of the rat brain were chemicallydestroyed by injecting a very small amount of 6-hydroxydopamine toinduce motor imbalance. Two weeks later, dopamine cells of fetal brainwere transplanted into the lesioned side of the caudate nucleus of therat brain and an attempt was made to improve the motor trouble.Specifically, beginning on the day of transplantation, the compound ofthe invention was intraperitoneally administered every day over 2 weeks,and the activity of the compounds of the invention on the improvement ofthe motor imbalance and the growth of the transplanted cells wereexamined. It was found that the compounds of the invention have apromoting effect on the improvement of the motor trouble.

Rats and mice having a nerve trouble by mercury poisoning were preparedand the activity of the compounds of the invention was tested. Thecompounds of the invention were found to have a promoting effect on theimprovement of the condition and recovery to a normal condition, acurative effect on chemical-induced disorders and an effect of improvingand recovering learning and memory.

Thus, it has been made clear that the compounds of this invention areuseful as agents for improving or curing various neurological diseasesof mammals, such as troubles in peripheral and central nerves, and alsoas agents for improving learning and memory.

Various types of neuropathy including, for example, various peripheralnerve disorders accompanied by motorgenic, sensory or objective flexretardation, and alcohol-induced or drug-induced, diabetic andmetabolic, or idiopathic peripheral nerve disorders, includingtraumatic, inflammatory or immunological nerve root lesions may be citedas such neurological diseases. More specific examples include facialpalsy, sciatic nerve paralysis, spinal muscular atrophy, musculardystrophy, myasthenia gravis, multiple sclerosis, amyotrophic lateralsclerosis, acute disseminated cerebromyelitis, Guillan-Barre syndrome,postvaccinal encephalomyelitis, SMON disease, dementia, Alzheimersyndrome, a condition after cranial injury, cerebral spinal injury,neural injury disorders which occur in cerebral ischemia, sequela ofcerebral infarction or cerebral hemorrhage, and rheumatism.

By a toxicity test, the compounds of this invention were found to haveonly weak toxicity and side effects, and be used as safe and usefulmedicines.

EXPERIMENTAL EXAMPLE 1

The effects of the compounds of this invention on neuroblastoma cellswere examined by the following method.

Mouse neuro 2a cells in the logarithmic growth period in the Dulbecco'smodified Eagle's medium DMEM, containing 100 units/ml of penicillin Gsodium and 100 micrograms/ml of streptomycin sulfate]containing 10 % ofFCS were seeded in a 48-well plate so that the number of cells was 1,000cells/well, and cultured for one day in 0.25 ml of the culture fluid ineach well in an incubator containing 5 % of carbon dioxide gas in air at37° C. Then, a 4 % aqueous glutaraldehyde solution in the same amount asa medium (0.25 ml) was added, and the culture fluid was left to stand atroom temperature for 2 hours to fix the cells. After washing with water,a 0.05 % aqueous solution of methylene blue was added to stain the cellsUnder a microscope, the number of cells containing outgrown neurites(cells having at least one neurite with a length of at least two timesas large as the long diameter of the cell) was counted visually, and theproportion of these cells in the entire cells was calculated. The wellwas observed over 5 or more visual fields (at least 2 % of the entiresurface area of the well) continuous to the left and right from a markput at the center of the well, and more than 200 cells was counted. Onedrug compound was used in 6 different concentrations at most, and threeruns were conducted for each concentrations. The results were expressedas a mean ±S.D., and the results are shown in Table 12.

Mouse neuroblastoma cells NS-20Y were similarly cultured in a dishcoated with polyornithine, and the effects of the compounds wereexamined. The results obtained after 24 hours and 48 hours from thestart of culturing are shown in Table 13.

                  TABLE 12                                                        ______________________________________                                        Action on neuro - 2a                                                                         Number of cells having neurites with a                                        length at least two times the diameter of                      Run            each cell/total number of cells, %                             No.  Compound  (concentration of the compound)                                ______________________________________                                         1   1034      3.9 ± 2.8 (0.03 mM), 7.6 ± 2.1 (0.1 mM),                                11.3 ± 1.6 (0.3 mM)                                               312      4.5 ± 0.4 (0.03 mM), 9.7 ± 0.9 (0.1 mM)                       isaxonine 26.7 ± 7.7 (10 mM)                                               control   1.8 ± 0.8                                                    2    128      9.9 ± 0.6 (0.3 mM), 9.1 ± 0.7 (0.5 mM),                                 19.8 ± 2.8 (1 mM), 14.3 ± 2.4 (2 mM)                           208      7.2 ± 2.3 (0.5 mM), 10.6 ± 1.5 (1 mM),                                  11.1 ± 1.2 (2 mM), 8.0 ± 4.0 (3 mM)                            168      23.8 ± 2 (0.05 mM), 35.7 ± 0.8 (0.1 mM),                                24.4 ± 6.9 (0.2 mM), 14.6 ± 4.3 (0.3 mM)                      isaxonine 28.5 ± 5.4 (10 mM)                                               control   1.4 ± 0.2                                                    3    384      10.4 ± 2.5 (0.3 mM), 10.8 ± 7.2 (1 mM)                         392      14.6 ± 6.0 (0.1 mM), 30.9 ± 5.7 (0.3 mM),                               23.8 ± 4.2 (1 mM), 11.1 ± 9.7 (3 mM)                           700      5.9 ± 1.4 (0.1 mM), 6.4 ± 1.4 (0.3 mM)                        isaxonine 30.8 ± 2.9 (10 mM)                                               control   3.2 ± 1.6                                                    4    416      13.2 ± 1.3 (0.1 mM), 10.8 ± 1.5 (0.3 mM)                       320      7.2 ± 0.2 (0.1 mM), 8.5 ± 1.1 (0.3 mM)                         328      6.6 ± 0.5 (0.01 mM), 10.2 ± 8.2 (0.03 mM),                              28.0 ± 6.8 (0.1 mM), 10.6 ± 3.4 (0.3 mM)                       400      11.4 ± 4.3 (0.3 mM), 16.0 ± 2.7 (1 mM)                        isaxonine 30.7 ± 5.9 (10 mM)                                               control   2.9 ± 1.9                                                    5    136      11.6 ± 6.3 (0.1 mM), 12.1 ± 2.9 (0.3 mM)                       628      10.2 ± 1.3 (0.03 mM), 13.4 ± 3.2 (0.1 mM),                              12.6 ± 3.2 (0.3 mM), 10.0 ± 3.9 (1 mM)                         144      13.7 ± 7.8 (0.1 mM), 33.8 ± 8.6 (0.3 mM)                       408      9.1 ± 1.8 (0.1 mM), 9.6 ± 3.9 (0.3 mM)                        isaxonine 23.8 ± 4.0 (10 mM)                                               control   1.8 ± 0.8                                                    6    264      5.2 ± 3.1 (0.1 mM), 8.7 ± 1.6 (0.3 mM),                                 15.2 ± 3.2 (1 mM), 7.2 ± 1.8 (3 mM)                            424      4.5 ± 1.4 (0.03 mM), 7.6 ± 1.3 (0.1 mM)                       isaxonine 27.3 ± 4.4 (10 mM)                                               control   2.1 ± 0.5                                                    7    360      6.5 ± 0.7 (0.03 mM), 10.0 ± 0.7 (0.1 mM)                       272      4.8 ± 1.3 (0.03 mM), 30.9 ± 2.8 (0.1 mM),                               15.9 ± 0.5 (0.3 mM), 17.0 ± 4.3 (1 mM)                         676      4.2 ± 2.1 (1.0 mM), 6.0 ± 1.1 (0.3 mM)                        isaxonine 27.3 ± 4.4 (10 mM)                                               control   1.8 ± 0.5                                                    8    240      19.8 ± 5.7 (0.03 mM), 38.7 ± 4.5 (0.1 mM),                              33.2 ± 0.9 (0.3 mM), 30.9 ± 5.9 (1 mM)                         296      44.4 ± 5.5 (0.1 mM), 22.4 ± 3.0 (0.3 mM)                       170      33.5 ± 2.4 (0.1 mM), 31.0 ± 4.6 (0.3 mM)                       224      4.6 ± 1.7 (0.03 mM), 5.5 ± 1.5 (0.1 mM)                        432      2.9 ± 1.0 (0.1 mM), 3.6 ± 1.7 (0.3 mM)                         604      18.7 ± 4.1 (0.1 mM), 24.6 ± 2.9 (0.3 mM)                       612      13.8 ± 1.5 (0.01 mM), 19.1 ± 3.0 (0.03 mM),                             19.4 ± 3.9 (0.1 mM), 22.4 ± 2.4 (0.3 mM)                      isaxonine 21.1 ± 0.6 (10 mM)                                               control   1.7 ± 1.3                                                    9    636      12.1 ± 3.4 (0.03 mM), 8.9 ± 5.2 (0.1 mM)                       176      5.3 ± 1.9 (0.03 mM), 3.2 ± 3.1 (0.1 mM)                        184      18.8 ± 4.7 (0.1 mM), 16.0 ± 2.4 (0.3 mM)                       644      26.1 ± 7.3 (0.03 mM), 14.7 ± 7.3 (0.1 mM)                       620     4.7 ± 0.4 (0.01 mM), 4.0 ± 1.3 (0.03 mM)                       652      6.1 ± 0.6 (0.03 mM), 12.5 ± 2.8 (0.1 mM)                       152      6.2 ± 2.3 (0.03 mM), 33.8 ± 4.7 (0.1 mM)                      isaxonine 27.5 ± 0.8 (10 mM)                                               control   1.4 ± 0.7                                                   10    376      13.6 ± 1.2 (0.03 mM), 14.7 ± 1.5 (0.1 mM),                              17.2 ± 1.4 (0.3 mM), 16.4 ± 3.0 (1 mM)                         200      4.2 ± 1.6 (0.01 mM), 7.6 ± 1.6 (0.03 mM)                       192      12.1 ± 1.5 (0.3 mM), 14.6 ± 1.0 (1 mM)                        isaxonine 27.8 ± 2.5 (10 mM)                                               control   3.0 ± 0.8                                                   11    660      13.5 ± 1.3 (0.03 mM), 9.1 ± 3.7 (0.1 mM)                       304      38.1 ± 1.6 (0.1 mM), 15.3 ± 6.3 (0.3 mM)                      isaxonine 30.7 ± 3.8 (10 mM)                                               control   2.6 ± 0.5                                                   12    692      5.8 ± 0.9 (0.03 mM), 11.1 ± 2.9 (0.1 mM)                       160      11.3 ± 6.3 (0.1 mM), 6.7 ±  4.3 (0.3 mM)                      isaxonine 23.9 ± 1.8 (10 mM)                                               control   1.5 ± 1.5                                                   13    668      5.6 ± 0.8 (0.01 mM), 4.8 ± 0.4 (0.03 mM),                               5.2 ± 0.7 (0.1 mM), 4.1 ± 2.5 (0.3 mM)                         684      3.8 ± 0.5 (0.01 mM), 5.8 ± 2.0 (0.03 mM),                               16.4 ± 2.8 (0.1 mM)                                               280      4.5 ± 1.2 (0.03 mM), 17.2 ± 1.3 (0.1 mM),                               13.4 ± 3.5 (0.3 mM), 17.4 ± 2.6 (1 mM)                        isaxonine 15.8 ± 2.2 (3 mM)                                                control   2.9 ± 1.0                                                   14    368      3.5 ± 0.5 (0.03 mM), 9.0 ± 1.8 (0.1 mM)                        344      3.6 ± 0.7 (0.01 mM), 4.0 ± 1.7 (0.03 mM),                               4.7 ± 1.8 (0.1 mM), 4.5 ± 2.1 (0.3 mM)                        isaxonine 16.8 ± 3.4 (3 mM)                                                control   2.6 ± 0.6                                                   15    336      5.8 ± 2.4 (0.1 mM), 6.3 ± 2.8 (0.3 mM)                         120      4.9 ± 1.0 (0.1 mM), 7.5 ± 4.1 (0.3 mM)                         232      3.9 ± 1.8 (0.03 mM), 18.7 ± 5.2 (0.1 mM)                       248      4.3 ± 0.4 (0.03 mM), 25.4 ± 3.0 (0.1 mM),                               21.5 ± 5.7 (0.3 mM), 17.4 ± 4.5 (1 mM)                        isaxonine 19.4 ± 3.1 (3 mM)                                                control   3.2 ± 1.2                                                   16    812      3.5 ± 0.5 (0.1 mM), 3.4 ± 0.5 (0.3 mM)                         816      4.7 ± 2.1 (0.03 mM), 4.0 ± 0.3 (0.1 mM)                        820      8.4 ± 1.1 (1 mM), 8.8 ± 2.3 (3 mM)                             800      11.4 ± 1.2 (0.3 mM), 25.7 ± 1.9 (1 mM),                                 22.3 ± 0.7 (3 mM), 16.9 ± 0.8 (10 mM)                          828      7.3 ± 1.6 (0.3 mM), 6.1 ± 2.0 (1 mM)                          isaxonine 27.0 ± 3.8 (10 mM)                                               control   2.3 ± 0.4                                                   17   1014      4.7 ± 0.7 (0.1 mM), 7.6 ± 1.5 (0.3 mM)                        1122      4.2 ± 2.1 (0.01 mM), 10.2 ± 3.8 (0.03 mM)                     1026      3.5 ± 0.5 (0.03 mM), 5.6 ±  2.2 (0.1 mM)                      1130      1.8 ± 0.5 (0.03 mM), 2.0 ± 0.3 (0.1 mM)                       1038      2.2 ± 0.4 (0.03 mM), 2.9 ± 0.3 (0.1 mM)                       isaxonine 27.4 ± 2.4 (10 mM)                                               control   1.8 ± 1.3                                                   18    112      4.8 ± 0.1 (0.03 mM), 18.6 ± 5.2 (0.1 mM),                               2.6 ± 0.6 (0.3 mM), 7.6 ± 4.9 (1 mM)                           216      3.7 ± 0.4 (0.01 mM), 6.3 ± 2.4 (0.03 mM),                               26.6 ± 5.6 (0.1 mM)                                              isaxonine 23.3 ± 2.9 (10 mM)                                               control   2.3 ± 0.6                                                   19    104      2.5 ± 0.8 (0.03 mM), 4.1 ± 1.5 (0.1 mM),                                7.7 ± 3.8 (0.3 mM), 3.6 ± 1.4 (1 mM)                           352      3.2 ± 1.9 (0.1 mM), 9.9 ± 1.6 (0.3 mM)                        isaxonine 22.6 ± 0.5 (10 mM)                                               control   1.8 ± 1.4                                                   20    288      1.4 ± 0.1 (0.03 mM), 3.3 ± 0.9 (0.1 mM),                                3.8 ± 1.9 (0.3 mM), 5.1 ± 2.7 (1 mM)                           256      4.5 ± 0.6 (0.03 mM), 17.9 ± 6.3 (0.1 mM),                               21.6 ± 4.9 (0.3 mM), 16.6 ± 2.5 (1 mM)                        isaxonine 19.4 ± 3.1 (10 mM)                                               control   2.2 ± 1.0                                                   21   1086      1.9 ± 1.8 (0.03 mM), 3.1 ± 1.3 (0.1 mM),                                8.7 ± 0.8 (0.3 mM), 17.4 ± 1.1 (1 mM)                         1110      3.4 ± 1.1 (0.01 mM), 4.4 ± 0.3 (0.03 mM),                               6.3 ± 4.4 (0.1 mM), 16.5 ± 2.1 (0.3 mM)                       isaxonine 30.2 ± 3.5 (10 mM)                                               control   2.6 ± 1.0                                                   22   1090      3.7 ± 1.0 (0.01 mM), 5.7 ± 0.6 (0.03 mM),                               12.2 ± 2.5 (0.1 mM), 10.3 ± 0.9 (0.3 mM)                      1158      9.9 ± 1.4 (0.03 mM), 18.4 ± 3.0 (0.1 mM),                               22.1 ± 6.7 (0.3 mM), 19.1 ± 2.7 (1 mM)                        isaxonine 26.7 ± 3.3 (10 mM)                                               control   2.4 ± 1.6                                                   23    804      9.4 ± 1.3 (0.3 mM), 13.0 ± 2.1 (0.5 mM),                                26.1 ± 6.8 (1 mM), 18.8 ± 3.1 (2 mM)                          isaxonine 28.5 ± 5.4 (10 mM)                                               control   1.4 ± 0.2                                                   24   1094      5.4 ± 1.9 (0.1 mM), 16.9 ± 1.2 (0.3 mM),                                10.9 ± 1.1 (1 mM)                                                1098      5.3 ± 1.4 (0.01 mM), 10.2 ± 0.9 (0.03 mM),                              5.7 ± 2.0 (0.1 mM)                                               isaxonine 15.7 ± 4.1 (3 mM)                                                control   1.2 ± 1.1                                                   25   1162      4.7 ± 3.0 (0.03 mM), 5.9 ± 1.9 (0.1 mM)                       1102      11.9 ± 0.7 (0.1 mM), 10.1 ± 3.0 (0.3 mM)                      isaxonine 26.7 ± 7.7 (10 mM)                                               control   1.8 ± 0.8                                                   26    138      6.3 ± 1.8 (0.03 mM), 12.6 ± 4.1 (0.1 mM)                      2004      6.6 ± 2.2 (0.03 mM), 30.2 ± 6.4 (0.1 mM)                       171-3    28.8 ± 3.1 (0.1 mM), 19.5 ± 7.0 (0.3 mM)                      2052      4.6 ± 2.1 (0.01 mM), 3.7 ± 0.4 (0.03 mM)                      2060      3.6 ± 0.1 (0.03 mM), 7.6 ± 0.7 (1 mM)                         2070      5.6 ± 3.9 (0.1 mM), 11.7 ± 3.1 (0.3 mM)                       2076      4.8 ± 1.4 (0.01 mM), 1.9 ± 1.3 (0.03 mM)                      isaxonine 31.4 ± 5.5 (10 mM)                                               control   2.5 ± 0.2                                                   27   2084      11.1 ± 2.2 (0.03 mM), 17.6 ± 6.6 (0.1 mM)                     2092      23.9 ± 0.4 (0.1 mM), 11.0 ± 3.9 (1 mM)                        2100      4.4 ± 0.8 (0.03 mM), 4.7 ± 1.4 (0.1 mM)                       2108      4.8 ± 2.0 (0.03 mM), 13.5 ± 0.1 (1 mM)                         146      8.7 ± 2.0 (0.03 mM), 40.0 ± 6.1 (0.1 mM)                       147-1    6.6 ± 0.4 (0.03 mM), 30.5 ± 6.1 (0.1 mM)                      2116      34.2 ± 3.8 (0.1 mM), 8.2 ± 3.6 (0.3 mM)                       2124      12.5 ± 5.3 (0.03 mM), 31.7 ± 7.0 (0.1 mM)                     isaxonine 31.4 ± 5.5 (10 mM)                                               control   2.5 ± 0.2                                                   28    165      41.0 ± 0.7 (0.1 mM), 12.4 ± 1.8 (0.3 mM)                       166      36.8 ± 7.1 (0.1 mM), 13.4 ± 4.0 (0.3 mM)                       167      22.5 ± 3.4 (0.1 mM), 9.3 ± 2.3 (0.3 mM)                        169      34.1 ± 5.7 (0.1 mM), 16.6 ± 5.2 (0.3 mM)                       171      37.1 ± 1.9 (0.1 mM), 8.8 ± 2.6 (0.3 mM)                        171-1    36.4 ± 7.8 (0.1 mM), 15.2 ± 3.1 (0.3 mM)                       171-11   36.8 ± 7.1 (0.1 mM), 14.3 ± 3.0 (0.3 mM)                      isaxonine 21.0 ± 2.3 (10 mM)                                               control   2.5 ± 0.2                                                   29   2132      32.6 ± 4.4 (0.1 mM), 31.7 ± 5.0 (0.3 mM)                      2140      5.4 ± 3.9 (0.03 mM), 17.0 ± 1.2 (0.1 mM)                      2148      4.5 ± 1.3 (0.03 mM), 4.2 ± 1.2 (0.1 mM)                       2156      8.6 ± 1.0 (0.03 mM), 19.6 ± 5.3 (0.1 mM)                       307-1    3.6 ± 0.4 (0.03 mM), 9.0 ± 2.5 (0.3 mM)                       2164      4.6 ± 1.1 (0.1 mM), 11.7 ± 0.7 (1 mM)                         isaxonine 21.0 ± 2.3 (10 mM)                                               control   3.1 ± 1.2                                                   30    154      5.2 ± 1.5 (0.03 mM), 16.2 ± 2.1 (0.1 mM)                      2174      2.5 ± 1.0 (0.01 mM)                                              2182      8.0 ± 3.2 (0.03 mM), 2.7 ± 0.9 (0.1 mM)                       2188      2.4 ± 0.9 (0.1 mM), 3.8 ± 1.1 (0.3 mM)                        2194      9.5 ± 3.5 (0.1 mM), 7.6 ± 2.8 (0.3 mM)                        2202      2.2 ± 2.0 (0.1 mM)                                               2210      9.5 ± 2.0 (0.03 mM), 9.5 ± 1.9 (0.1 mM)                       isaxonine 19.4 ± 2.4 (10 mM)                                               control   1.7 ± 0.9                                                   31   2218      9.7 ± 1.8 (0.03 mM), 11.4 ± 6.1 (0.1 mM)                       662      3.1 ± 1.6 (0.1 mM), 2.6 ± 0.9 (0.3 mM)                        2226      6.4 ± 3.3 (0.03 mM), 15.4 ± 3.9 (0.1 mM)                      2234      5.1 ± 3.2 (0.03 mM), 5.7 ± 2.8 (0.1 mM)                       2242      3.3 ± 0.9 (0.03 mM), 24.8 ± 2.9 (0.1 mM)                      2250      10.9 ± 3.9 (0.1 mM), 19.2 ± 1.0 (0.3 mM)                      isaxonine 19.4 ± 2.4 (10 mM)                                               control   1.7 ± 0.9                                                   32   2260      2.2 ± 0.3 (0.03 mM), 2.3 ± 0.5 (0.1 mM)                       2270      14.7 ± 5.1 (0.03 mM), 19.9 ± 4.2 (0.1 mM)                               21.3 ± 3.5 (0.3 mM), 15.2 ± 1.5 (1 mM)                        2278      13.9 ± 6.3 (0.03 mM), 12.5 ± 1.3 (0.1 mM)                     2286      9.7 ± 5.4 (0.03 mM), 8.4 ± 0.8 (0.1 mM)                       2294      3.7 ± 0.9 (0.03 mM), 8.1 ± 1.6 (0.1 mM)                       2302      8.0 ± 2.7 (0.03 mM), 8.2 ± 4.7 (0.1 mM)                       isaxonine 19.4 ± 2.4 (10 mM)                                               control   1.7 ± 0.9                                                   33   2012      6.6 ± 1.2 (0.03 mM), 6.6 ± 3.1 (0.3 mM)                       2020      4.6 ± 1.1 (0.03 mM), 33.8 ± 9.6 (0.1 mM),                               30.5 ± 9.5 (0.3 mM), 15.1 ± 5.0 (1 mM)                        2028      4.0 ± 0.8 (0.03 mM), 12.5 ± 1.2 (0.1 mM)                      2036      3.9 ± 0.8 (0.03 mM), 5.4 ± 1.1 (0.1 mM)                       2044      3.7 ± 0.7 (0.01 mM), 10.3 ± 4.7 (0.1 mM)                      isaxonine 19.5 ± 3.6 (10 mM)                                               control   2.7 ± 0.6                                                   34   2310      8.3 ±  1.8 (0.1 mM), 12.1 ± 3.6 (0.3 mM)                      2318      7.7 ± 1.4 (0.03 mM), 35.1 ± 1.3 (0.1 mM),                               18.6 ± 5.2 (0.3 mM), 8.8 ± 1.3 (1 mM)                         2326      4.6 ± 1.4 (0.03 mM), 8.3 ± 2.6 (0.1 mM)                       2334      13.2 ± 0.2 (0.03 mM), 16.7 ± 0.8 (0.1 mM)                     2342      5.9 ± 2.1 (0.03 mM), 11.4 ± 1.4 (0.1 mM)                      2350      5.9 ± 1.5 (0.3 mM), 8.3 ± 2.0 (1 mM)                           154-2    3.9 ± 0.6 (0.03 mM), 8.9 ± 2.4 (0.1 mM)                        171-5    7.2 ± 1.1 (0.01 mM), 28.4 ± 2.2 (0.1 mM),                               32.7 ± 0.6 (0.3 mM), 14.0 ± 4.1 (1 mM)                        isaxonine 16.1 ± 0.6 (10 mM)                                               control   3.3 ± 0.6                                                   35   3104      2.8 ± 0.8 (0.03 mM), 4.0 ± 2.2 (0.1 mM),                                7.2 ± 2.8 (0.3 mM), 6.1 ± 1.6 (1 mM)                          isaxonine 16.8 ± 3.4 (3 mM)                                                control   2.6 ± 0.6                                                   36   3144      20.8 ± 4.7 (0.03 mM), 34.1 ± 3.8 (0.1 mM),                              44.5 ± 9.7 (0.3 mM), 32.2 ± 1.6 (1 mM)                        isaxonine 30.8 ± 2.9 (10 mM)                                               control   3.2 ± 1.6                                                   37   3200      3.6 ± 0.5 (0.03 mM)                                              isaxonine 23.3 ± 2.9 (10 mM)                                               control   2.3 ± 0.6                                                   38   3300      6.1 ± 1.2 (0.3 mM), 7.8 ± 1.0 (1 mM)                          3200      2.7 ± 0.7 (0.01 mM), 2.5 ± 2.3 (0.03 mM)                      isaxonine 19.4 ± 3.1 (3 mM)                                                control   3.2 ± 1.2                                                   39   3136      5.8 ± 0.6 (0.01 mM), 13.8 ± 4.8 (0.03 mM),                              20.9 ± 5.3 (0.1 mM), 7.1 ± 3.0 (0.3 mM)                       isaxonine 22.6 ± 0.5 (10 mM)                                               control   1.8 ± 1.4                                                   40   3128      14.2 ± 1.9 (0.1 mM), 11.9 ± 4.5 (0.3 mM)                      3112      6.3 ± 0.4 (0.03 mM), 6.2 ± 3.4 (0.1 mM)                       3152      11.4 ± 3.1 (0.03 mM), 6.8 ± 4.2 (0.1 mM)                      3176      7.3 ± 3.3 (0.03 mM), 23.1 ± 4.8 (0.1 mM),                               21.2 ± 4.9 (0.3 mM), 14.6 ± 5.0 (1 mM)                        3184      3.7 ± 1.1 (0.03 mM), 13.9 ± 2.3 (0.1 mM),                               18.4 ± 1.9 (0.3 mM), 17.0 ± 2.1 (1 mM)                        3192      9.7 ± 1.1 (0.1 mM), 3.7 ± 3.2 (0.3 mM)                        isaxonine 19.4 ± 3.1 (10 mM)                                               control   2.2 ± 1.0                                                   41   3404      3.3 ± 1.3 (0.03 mM), 3.4 ± 1.4 (0.3 mM)                       3412      2.9 ± 0.9 (0.03 mM), 20.6 ± 8.2 (0.1 mM)                      3420      4.2 ± 1.9 (0.03 mM), 8.7 ± 2.3 (0.1 mM)                       isaxonine 19.4 ± 2.4 (10 mM)                                               control   1.7 ± 0.9                                                   42    298      2.7 ± 1.7 (0.1 mM), 6.1 ± 5.6 (0.3 mM)                         306      7.7 ± 0.5 (0.03 mM), 2.8 ± 0.8 (0.1 mM)                        242      17.0 ± 2.3 (0.1 mM), 12.8 ± 6.3 (0.3 mM)                                9.4 ± 3.9 (1 mM)                                                  150      9.3 ± 1.9 (0.03 mM), 13.6 ± 1.2 (0.1 mM)                                6.6 ± 3.0 (0.3 mM)                                                171-9    24.4 ± 6.6 (0.1 mM), 7.1 ± 2.9 (0.3 mM)                       isaxonine 12.1 ± 1.6 (3 mM)                                                control   2.4 ± 0.4                                                   43    171-11   5.9 ± 0.9 (0.03 mM), 22.1 ± 2.3 (0.1 mM)                                29.2 ± 1.5 (0.3 mM), 31.7 ± 5.9 (1 mM)                         170-2    14.7 ± 1.1 (0.1 mM), 5.6 ± 2.1 (0.3 mM)                                 13.9 ± 3.0 (1 mM)                                                 171-7    8.5 ± 1.0 (0.03 mM), 6.7 ± 3.1 (0.1 mM)                        171-12   13.3 ± 1.1 (0.1 mM), 10.7 ± 4.2 (0.3 mM)                                12.7 ± 0.9 (1 mM)                                                isaxonine 14.9 ± 1.9 (10 mM)                                               control   2.5 ± 1.0                                                   44   2022-1    23.1 ± 4.8 (0.1 mM), 18.1 ± 2.8 (0.3 mM)                                19.8 ± 2.1 (1 mM)                                                2023-1    8.3 ± 2.1 (0.1 mM), 7.0 ± 0.5 (0.3 mM)                        isaxonine 20.1 ± 3.0 (10 mM)                                               control   3.2 ± 0.9                                                   ______________________________________                                    

                  TABLE 13                                                        ______________________________________                                        Activity on NS-20Y cells                                                               Number of cells in which neurites                                             appeared/total number of cells                                                (concentration of the compound)                                      Compound   24 hours       48 hours                                            ______________________________________                                        112        4/51    (0.025 mM)                                                                              9/50   (0.025 mM)                                                             4/49   (0.01 mM)                                 control    0/51              1/51                                             120        23/50   (0.5 mM)  4/50   (0.5 mM)                                  control    1/49              0/50                                             144        37/50   (0.1 mM)  31/50  (0.1 mM)                                                               8/52   (0.05 mM)                                 control    0/50              1/50                                                                          6/50   (0.025 mM)                                152        3/50    (0.05 mM) 2/50   (0.025 mM)                                control    0/50              0/50                                             160        10/53   (0.5 mM)  2/50   (0.5 mM)                                  control    0/50              0/50                                             168        26/50   (0.1 mM)  20/55  (0.1 mM)                                             12/50   (0.25 mM)                                                  control    3/50              2/50                                             208        27/53   (0.1 mM)  28/50  (0.1 mM)                                             17/51   (0.25 mM)                                                  control    1/50              0/52                                             128        23/55   (1.0 mM)  31/50  (0.3 mM)                                             4/49    (0.3 mM)  21/50  (0.5 mM)                                  control    3/50              4/50                                             216        3/49    (0.025 mM)                                                                              24/50  (0.025 mM)                                                             20/50  (0.05 mM)                                 control    0/51              1/50                                             232        2/50    (0.025 mM)                                                                              2/49   (0.01 mM)                                 control    0/51              0/50                                             240        4/50    (0.2 mM)  3/50   (0.2 mM)                                  control    0/50              0/50                                             248        3/49    (0.1 mM)  2/50   (0.05 mM)                                 control    0/49              0/50                                             256        5/51    (0.2 mM)  2/48   (0.05 mM)                                 control    0/51              0/50                                             272        33/50   (0.1 mM)  17/50  (0.1 mM)                                             24/50   (0.2 mM)                                                   control    0/50              0/51                                             280        3/50    (0.2 mM)  8/53   (0.1 mM)                                  control    0/50              1/53                                             288        2/52    (0.1 mM)  2/50   (0.1 mM)                                  control    0/50              0/50                                             296        9/49    (0.1 mM)  2/50   (0.1 mM)                                  control    0/50              0/48                                             304        40/50   (0.1 mM)  3/50   (0.01 mM)                                 control    0/50              0/51                                             328        32/50   (0.1 mM)  8/50   (0.025 mM)                                                             12/51  (0.1 mM)                                  control    0/51              0/50                                             336        3/54    (0.2 mM)  2/50   (0.5 mM)                                  control    0/52              0/50                                             344        3/51    (0.2 mM)  2/49   (0.5 mM)                                  control    0/50              0/51                                             368        14/50   (0.1 mM)  8/51   (0.05 mM)                                                              5/50   (0.1 mM)                                  control    0/50              0/50                                             376        2/50    (0.2 mM)  2/50   (0.1 mM)                                  control    0/50              0/50                                             392        8/50    (0.1 mM)  6/51   (0.05 mM)                                                              3/43   (0.1 mM)                                  control    0/52              0/50                                             612        2/50    (0.1 mM)  2/50   (0.1 mM)                                  control    0.50              1/51                                             668        2/50    (0.1 mM)  2/50   (0.05 mM)                                 control    0/50              0/50                                             684        2.50    (0.1 mM)  2/50   (0.05 mM)                                 control    0/53              0/50                                             1094       7/48    (0.4 mM)  2/50   (0. mM)                                              4/54    (0.1 mM)                                                   control    2/50              1/50                                             1026       31/50   (0.1 mM)  2/50   (0.02 mM)                                            4/50    (0.02 mM)                                                  control    2/50              1/50                                             1086       4/50    (0.4 mM)  2/50   (0.02 mM)                                 control    2/50              1/50                                             1090       21/50   (0.1 mM)  3/50   (0.1 mM)                                             4/50    (0.02 mM)                                                  control    1/50              1/50                                             1014       9/50    (0.4 mM)  6/50   (0.4 mM)                                             3/50    (0.1 mM)                                                   control    2/50              2/50                                             384        8/50    (0.4 mM)  3/50   (0.4 mM)                                  control    2/50              1/50                                             416        11/50   (0.4 mM)  2/50   (0.1 mM)                                             7/50    (0.1 mM)                                                   control    1/50              0/50                                             320        8/50    (0.1 mM)  6/50   (0.1 mM)                                  control    2/50              1/50                                             400        30/53   (0.4 mM)  3/48   (0.4 mM)                                             9/50    (0.1 mM)  3/50   (0.1 mM)                                  control    2/50              1/50                                             136        42/50   (0.4 mM)  15/50  (0.4 mM)                                             9/50    (0.1 mM)                                                   control    3/50              1/50                                             264        8/48    (0.4 mM)  4/50   (0.4 mM)                                  control    2/50              1/50                                             424        16/50   (0.4 mM)  3/50   (0.4 mM)                                  control    3/52              1/50                                             360        18/50   (0.1 mM)  4/50   (0.1 mM)                                             8/50    (0.02 mM)                                                  control    3/50              1/50                                             224        6/50    (0.02 mM) 3/50   (0.02 mM)                                 control    1/50              1/50                                             432        7/50    (0.4 mM)  4/50   (0.4 mM)                                             7/50    (0.02 mM)                                                  control    2/50              2/50                                             200        4/50    (0.02 mM) 2/50   (0.02 mM)                                 control    2/50              1/50                                             192        23/50   (0.4 mM)  4/50   (0.4 mM)                                  control    2/50              1/50                                             176        8/50    (0.1 mM)  2/50   (0.02 mM)                                 control    1/50              0/50                                             184        8/50    (0.02 mM) 3/50   (0.02 mM)                                            5/48    (0.1 mM)                                                   control    1/52              1/50                                             628        9/50    (0.1 mM)  3/50   (0.1 mM)                                  control    3/50              1/50                                             700        6/50    (0.4 mM)  4/50   (0.1 mM)                                             4/53    (0.1 mM)                                                   control    2/50              1/50                                             660        5/50    (0.1 mM)  4/50   (0.1 mM)                                  control    2/50              1/50                                             604        7/50    (0.4 mM)  2/50   (0.02 mM)                                            6/50    (0.02 mM)                                                  control    2/50              1/50                                             804        8/55    (0.25 mM) 25/51  (0.5 mM)                                             7/50    (0.5 mM)  8/50   (0.25 mM)                                 control    4/50              0/50                                             168        26/50   (0.1 mM)  20/55  (0.1 mM)                                             12/50   (0.25 mM)                                                  control    3/50              2/50                                             208        27/53   (0.1 mM)  28/50  (0.1 mM)                                             17/51   (0.25 mM)                                                  control    1/50              0/52                                             820        5/53    (0.5 mM)  5/55   (0.25 mM)                                            4/50    (0.1 mM)  4/50   (0.1 mM)                                  control    3/50              0/50                                             828        10/58   (0.3 mM)  6/50   (0.3 mM)                                             5/59    (0.5 mM)  5/51   (0.5 mM)                                  control    2/50              2/51                                             812        11/50   (1.0 mM)  9/50   (0.3 mM)                                             9/50    (0.5 mM)  5/51   (0.5 mM)                                  control    2/53              2/50                                             3192       6/50    (0.02 mM) 4/50   (0.02 mM)                                 control    1/50              0/50                                             242        6/50    (0.4 mM)  11/50  (0.2 mM)                                             4/50    (0.2 mM)  6/50   (0.1 mM)                                  control    0/50              0/50                                             2022-1     12/50   (0.2 mM)  2/50   (0.1 mM)                                             5/50    (0.4 mM)                                                   control    0/50              0/50                                             2023-1     2/50    (0.1 mM)  2/50   (0.2 mM)                                  control    0/50              0/50                                              171-9     7/45    (0.4 mM)  2/50   (0.02 mM)                                 control    0/50              0/50                                              171-11    5/50    (0.3 mM)  2/50   (0.1 mM)                                  control    0/50              9/50                                              170-2     3/50    (0.1 mM)  2/50   (0.1 mM)                                  control    0/50              0/50                                              171-7     4/50    (0.1 mM)  2/50   (0.1 mM)                                  control    0/50              0/50                                             ______________________________________                                    

EXPERIMENTAL EXAMPLE 2 Therapeutic effect on rats with crushed sciaticnerves

The therapeutic effect of the compound of the invention was tested onrats having crushed sciatic nerves as a model of peripheral nervousdisorder using (1) a change in the action of the hind paw with thecrushed sciatic nerves and (2) a change in the weight of the muscle asan index of the course of degeneration and regeneration of peripheralnerves.

In the experiment, male Wistar rats (6 weeks old), seven per group, wereused. The sciatic nerves were crushed by a method similar to the methodof Yamatsu et al. (see Kiyomi Yamatsu, Takenori Kaneko, Akifumi Kitaharaand Isao Ohkawa, Journal of Japanese Pharmacological Society, 72,259-268 (1976) and the method of Hasegawa et al. (see Kazuo Hasegawa,Naoji Mikuni and Yutaka Sakai, Journal of Japanese PharmacologicalSociety, 74, 721-734 (1978). Specifically, under anesthesia withpentobarbital (40 mg/kg, i.p.), the left side sciatic nerve was exposedat the femur, and a specific site of the exposed sciatic nerve wascrushed for 30 seconds by using a hemostat. After the crushing, theoperation site was immediately sutured. Thereafter, vincristine known toretard the regeneration of the peripheral nerve was intraperitoneallyadministered in a dose of 100 g/kg once a week.

Compounds of the invention were selected as test drugs, and administeredintraperitoneally once a day from the day of crushing to 30th day fromthen. To a control group, only 0.9 % saline was administered.

(1) Functional change in the hind paw with crushed nerves

Twitch tension, which is a transient tension incident to contraction ofthe dominated muscles that occurs by electrical stimulation or the likeof motor nerves, as is the case with the interdigit distance to bedescribed, is considered to reflect functional changes of the nerves andmuscles.

Thus, 30 days later, under aesthesia with chloral hydrate (400 mg/kg,i.p.), the twitch tension of rats was measured by the method of Kern etal. J. Neurosci. Methods, 19, 259 (1987)]. Specifically, the hair on thehind paw of rats was shaven, and coated with Cardiocream (a product ofNihon Denko K.K.). Then, to the skin of the hind paw, electrodes with analligator were attached The cathode was attached to the rear portion ofthe trochiter, and the anode, to a site 1 cm rearwardly of the anodeelectrode and 1 cm toward its back. The rat was fixed on its back, andthe hind paw to be measured was fixed perpendicularly. A silk yarn,about 20 cm long, was connected at one end to the third efferent toejoint of the hind paw to be measured and at the other end to a tensiontransducer. Isotonic contractions of the third muscle digitus flexuswere recorded on a polygraph. Electrical stimulation was effected at avoltage of 100V for a continuous duration of 1 msec. with rectangularwaves at a frequency of 2 Hz. The static tension was 15 to 30 g, and 10stimulations were repeated 3 times with intervals of 15 seconds. Thecontracting force was expressed as tension (g). From the measured valuesof both paws, the recovery ratio (%, left/right) of the contractingforce of the paw with crushed nerves was calculated. The results areshown in Tables 14 and 15.

                  TABLE 14                                                        ______________________________________                                        Twitch tension                                                                           Dose     Number     Twitch tension*.sup. 1                         Compound   (mg/kg)  of cases   left/right (%)                                 ______________________________________                                        Saline     --       7          33.3 ± 7.0                                  168        10       7          48.4 ± 11.8*.sup.2                          168        30       8          51.2 ± 13.6*.sup.3                          296        30       8          48.1 ± 9.4*.sup.2                           ______________________________________                                         *.sup.1 mean ± S.D.,                                                       *.sup.2 p < 0.05,                                                             *.sup.3 p < 0.01                                                         

                  TABLE 15                                                        ______________________________________                                        Twitch tension                                                                                        Twitch tension                                               Dose   Number    left/right (%)                                        Compound (mg/kg)  of cases  18th days                                                                             23rd days                                 ______________________________________                                        Physio-  --       7         44.2 ± 17.6                                                                        49.8 ± 14.8                            logical                                                                       saline                                                                        3144     30       8         54.5 ± 17.1                                                                        57.9 ± 15.5                            ______________________________________                                    

The test compounds evidently increased the recovery of twitch tension,which is an electrophysiological index, and improved symptom, over thecontrol group.

The distance between digits was measured because this is a good indexwhich functionally shows the degeneration and regeneration of the nerveand its change can be measured with the lapse of time.

By a method similar to the method of Hasegawa [Hasegawa, K.,Experientia, 34, 750-751 (1978)], the distance between the first andfifth digits of the hind paw was measured.

The ratio of the measured distance to the interdigit distance in anormal hind paw was calculated and expressed in percentage (%). Theinterdigit distance of the hind paw with crushed nerves was less than50% of that in a normal hind paw immediately after the crushing.Recovery of the interdigit distance began 12 to 16 days later, and indrug-administered groups, there was evidently a tendency to acceleratedrecovery in comparison with the control group from about 17th day to thefinal day (26th).

One example is shown in Table 16.

                  TABLE 16                                                        ______________________________________                                        Therapeutic effect on rats having crushed sciatic nerves                                         Recovery of the                                                    Dose       interdigit distance                                        Compound  (mg/kg, i.p.)                                                                              18th days 23rd days                                    ______________________________________                                        Physio-   1 ml/kg      67.6 ± 16.1                                                                          76.5 ± 20.2                               logical                                                                       saline                                                                        3144      30           72.7 ± 14.0                                                                          83.8 ± 12.2                               ______________________________________                                    

(2) Change in the weight of muscle

It is known that removal of a nerve or its disorder causes atorphy ofthe muscle which is under its control, and the atrophy is graduallycured by re-control by the nerve. For this reason, a change in theweight of the muscle, which is quantitative, was selected as an index.Thirty days after the operation, the muscles extensor digitorum longusof both hind paws which are muscles under the control of sciatic nerveswere extracted under anesthesia, and their weights were measured. Theratio of the weight of the muscle extensor digitorum longus on thecrushed side to that of normal side was calculated and expressed inpercentage (%). The results are shown in Table 17.

                  TABLE 17                                                        ______________________________________                                                                       Weight of muscle                                                              extensor digito-                                          Dose     Number     rum longus*.sup. 1                             Compound   (mg/kg)  of cases   left/right (%)                                 ______________________________________                                        Saline     --       7          48.8 ± 6.4                                  168        10       7          52.1 ± 5.4                                  168        30       8          59.4 ± 11.8*.sup.2                          296        30       8          56.9 ± 9.7*.sup.2                           ______________________________________                                         *.sup.1 mean ± S.D.,                                                       *.sup.2 p < 0.05                                                         

The results show that the test compounds, in comparison with thecontrol, evidently increased the weight % of muscle extensor digitorumlongus.

Accordingly, these test compounds are useful as improvers andtherapeutic agents for peripheral nerve disorders.

EXPERIMENTAL EXAMPLE 3

Promoting effect on the improvement of motor imbalance due to injury ofthe rat's brain cells by transplantation of fetal cerebral cells.

Nigral dopaminergic nerve cells at the left side of the brain of 4-weekold female Wistar rats (body weight 100 g) were lesioned by injecting avery small quantity of 6-hydroxydopamine. The rats showed a tendency torotate spontaneously in a direction opposite to the lesioned side forseveral days, but no apparent abnormal action was observed after that.Upon administration of methamphethamine (5 mg/kg, i.p.) to the ratshaving the lesioned nigral dopaminergic nerve cells, they beganrotational movement toward the lesioned side.

After two weeks from the destruction by the administration of the drug,portions of the truncus corporis callosi containing dopamine cells(i.e., substantial nigra and the tagmentum at the abdomen side) were cutfrom the brain of a fetal rat of 14 to 17 days of age, cut finely, andtreated with trypsin. Then, the extracted tissues were incubated at 37°C. for 30 minutes, and the tissues were subjected to pipetting to form asuspension. Five microliters of the suspension was transplanted eachinto two sites of the caudate nucleus of the lesioned side (10microliters in total, about 105 cells)

Compound No. 168 of the invention was administered in a dose of 156mg/kg (i.p.) for 4 days from the day of transplantation, then with asuspension of 7 days, for 10 days in a dose of 50 mg/kg (i.p.) from the11th day. Compound No. 296 was administered in a dose of 153 mg/kg, andthen 50 mg/kg, in accordance with the same schedule.

Compound No. 3144 was also administered in accordance with the sameschedule in a dose of 135 mg/kg, and then 45 mg/kg.

The rotational movements induced by administration of methamphetaminewere examined 2 weeks and 1 week before, and 2 (or 3), 4, 6 and 8 weeksafter, the transplantation and the administration of the drug. Thenumber of rotational movements for the first one minute was counted atintervals of 10 minutes after the administration of methamphetamine, andthe total number of rotational movements counted six times was averagedto find a mean number of the rotational movements.

The results are shown in Table 18.

The results show that the test compounds are useful as improvers andtherapeutic agents for central nerve disorders.

                  TABLE 18                                                        ______________________________________                                        Com-                                                                          pound -1 W      3 W       4 W    6 W    8 W                                   ______________________________________                                        168   13.3 ± 7.8                                                                           9.1 ± 5.6                                                                            4.5 ± 4.5                                                                         1.5 ± 3.9                                                                         0.8 ± 2.1                          296   13.2 ± 4.1                                                                           8.4 ± 5.0                                                                            3.1 ± 3.4                                                                         0.9 ± 2.3                                                                         1.0 ± 1.5                          3144  14.1 ± 4.7                                                                           7.7 ± 4.7                                                                            4.0 ± 5.6                                                                         0.2 ± 2.2                                                                         1.1 ± 4.1                          Physio-                                                                             16.7 ± 9.1                                                                           11.2 ± 9.6                                                                           5.3 ± 8.3                                                                         2.8 ± 5.4                                                                         2.2 ± 6.0                          logical                                                                       saline                                                                        ______________________________________                                    

EXPERIMENTAL EXAMPLE 4

Improvement of learning and memory of mice with nerve disorder inducedby mercury poisoning, and recovery effect.

Male BalbC strain mice, 7 weeks old, were first caused to learn aT-shaped maze three times in a week so that they run straight from astarting point to a safety area. Then, methylmercury chloride (MMc forshort) was administered orally in a dose of 6 mg/kg/day for 6 days tomale Balb C strain mice (7 weeks old). A group of mice to which salinewas administered in a dose of 0.1 ml/10 g/day was used as a controlgroup. Beginning with the day next to the day of administering MMC,compounds of the invention were intraperitoneally administered over 10days. On the sixth day after administration of the drug (namely, on the12th day after start of the experiment), learning of the T-shaped mazewas resumed, and the running behaviors of the mice were observed Thenumber of mice which could be experimented in the T-shaped maze on the10th and 11th days after the resumption (21st and 22nd days after thestart of the experiment) was counted and expressed as a denominator. Thenumber of mice which ran to the safety area within 5 seconds at least 8times out of ten trial runnings was counted and expressed as anumerator. The decrease in the number of the test animals was due todeath by MMC poisoning. The time (seconds) required for the animals torun to the safety area was measured, and the mean±standard error (SE)was calculated.

The results demonstrate the effect of the compounds of the invention toimprove learning and memory of the mice and their recovery effect.

EXPERIMENTAL EXAMPLE 5

The acute toxicity of the compounds of the invention was examined by thefollowing method.

Male ddy-strain 5-week old mice, 4-6- per group, were used asexperimental animals. Each of the compounds was intraperitoneally(i.p.), and the toxicity of the compound was assessed 24 hours after theadministration. The results are shown in Table 19.

                  TABLE 19                                                        ______________________________________                                        Acute toxicity on mice                                                                      Estimated LD.sub.50                                             Compound      (mg/kg, i.p.)                                                   ______________________________________                                         128          >1000                                                            136          >1000                                                            144          >1000                                                            152          >1000                                                            168          >1000                                                            208          >1000                                                            392          500-1000                                                         328          >1000                                                            408          500-1000                                                         240          >1000                                                            296          >1000                                                            272          >1000                                                            170          >1000                                                            604           <500                                                            644          >1000                                                            304          >1000                                                            360          >1000                                                            376          500-1000                                                         424          >1000                                                            248          >1000                                                            216          >1000                                                           1090          500-1000                                                        1158           <250                                                            612          500-1000                                                         184          >1000                                                            192          500-1000                                                         280          500-1000                                                         232          >1000                                                            112          >1000                                                            120          >1000                                                            160          >1000                                                            176          >1000                                                            264          500-1000                                                         312          >1000                                                            320          >1000                                                            352          500-1000                                                         368          500-1000                                                         400          500-1000                                                         628          500-1000                                                         660          500-1000                                                         684          500-1000                                                         804          500-1000                                                         104          500-1000                                                         138          >1000                                                           2004          >1000                                                            146          >1000                                                            154          >1000                                                            147-1        >1000                                                            169          >1000                                                           2116          500-1000                                                        2124          >1000                                                            717-3        >1000                                                            256          >1000                                                            288          500-1000                                                        2132          >1000                                                           2140          >1000                                                           2020          500-1000                                                        2028          500-1000                                                        2044          500-1000                                                        2070          >1000                                                           2084          >1000                                                           2092          >1000                                                           2156          >1000                                                           2164          >1000                                                           2182          500-1000                                                        2210          500-1000                                                        2218          500-1000                                                        2242          500-1000                                                        2250          500-1000                                                        2270          >1000                                                           2278          500-1000                                                        2302          500-1000                                                        2318          500-1000                                                        2326          500-1000                                                        2342          500-1000                                                         154-2        500-1000                                                         171-5        >1000                                                           2310          500-1000                                                        2350          500-1000                                                        3104          >1000                                                           3122, 3144,   500-1000                                                        3176, 3184,                                                                   3192, 3412                                                                    and 3420                                                                      2318          >1000                                                           2334          >1000                                                            171-9        500-1000                                                         171-11       >1000                                                            170-2        500-1000                                                         170-12       >1000                                                           2022-1        >1000                                                           ______________________________________                                    

The compounds of general formulae (1), (2) and (3) provided by thisinvention have a promoting effect on the proliferation of nerve cellsand the formation and sprouting of neurites and a nerve regeneratingeffect and a motor function recovering effect in rats and mice havingnerve disorders, and can be used suitably for improving and curingneurological diseases such as disorders of peripheral nerves or centralnerves and dementia. They are expected to be used also suitably for therecovery, improving and curing of neurological diseases caused bynervous tissues and cells which have to do with perceptive and sensoryfunctions and an autonomic function.

It has been found that the compounds of the invention have biologicalactivities equal to, or higher than, those of isaxonine and mecobalaminas a control as shown in Experimental Examples 1 to 4 and Tables 12 to19. The toxicity of the compounds of this invention are generally weakas shown in Experimental Example 5. Thus, the compounds of thisinvention are generally considered to be highly active and highly safedrugs and very useful with weak toxicity.

We claim:
 1. A pyrimidine represented by the following formula (1), orits pharmaceutically acceptable salt, ##STR54## wherein R¹ represents ahydrogen atom or a lower alkyl group; X represents a group of theformula ##STR55## a group of the formula ##STR56## in which R²represents a hydrogen atom, a lower alkyl group, a phenyl group, abenzyl group or an alpha-(p-chlorophenyl)benzyl group, a group of theformula ##STR57## in which R³ corresponds to one or at least twoidentical or different substituents replacing one or at least twohydrogen atoms of identical or different methylene groups, andrepresents hydrogen, a lower alkyl group, a hydroxyl group, a phenylgroup optionally substituted by nitro, a benzyl group, a benzoyloxygroup, a benzoylamino group, a lower alkylamino group, a di-loweralkylamino group, the HO(C₆ H₅)₂ C-- group, a piperidino group, ahydroxy(lower alkyl) group,the C₆ H₅ SO₂ O-- group, a benzoyl groupoptionally substituted by halogen, a lower alkylsulfonylamide group or alower alkoxycarbonyl group, and n is a number of 4, 5, 6 or 7, a groupof the formula ##STR58## in which R⁴ represents a hydrogen atom, a loweralkyl group or a benzyl group, and R⁵ represents a lower alkyl group, alower acyl group, a 2-furoyl group, a benzyl group, a 4-piperidyl groupoptionally substituted by benzoyl, a phenethyl group, the ##STR59## or abenzoyl group optionally substituted by halogen or nitro, a group of the##STR60## a group of the formula ##STR61## group of the formula##STR62## or a group of the formula ##STR63## Y represents a group ofthe formula

    --CH.sub.2 R.sup.9

wherein R⁹ represents a hydrogen atom, a lower alkyl group, a loweralkoxy group, a lower alkylthio group, or a di-lower alkylamino group, agroup of the formula ##STR64## wherein R⁶ represents a hydrogen atom, alower alkyl group, a phenyl group, a benzyl group, a lower alkoxy groupor a 2-(N,N-dimethylamino)ethyl group, and R⁷ represents a lower alkylgroup, a lower acyl group, a cyclohexylcarbonyl group, a 2-furoyl group,a lower alkoxycarbonyl group, a cinnamoyl group, a benzyl group, loweralkoxy-lower alkyl-carbonyl group, a benzylcarbonyl group, a tosylgroup, a phenoxyacetyl group, a di-lower alkyl-carbamoyl group, a2-thenoyl group, a group o the formula ##STR65## a group of the formula##STR66## a group of the formula ##STR67## a group of the formula##STR68## a group of the formula ##STR69## a 4-lower alkylpiperazylgroup, or a benzoyl group optionally substituted by halogen, nitro,lower alkyl, lower alkoxy, amino, benzoylamino or phenyl, provided thatwhen R⁶ is a hydrogen atom, R⁷ is a benzoyl group, a group of theformula ##STR70## wherein R⁸ corresponds to a substituent replacing thehydrogen atom of the methylene group, and represents a hydrogen atom, alower alkyl group, a phenyl group or a benzyl group, and m is a numberof 4, 5, 6 or 7, a group of the formula ##STR71## a group of the formula##STR72## or a group of the formula ##STR73## and Z represents ahydrogen atom, a halogen atom, a lower alkyl group or a loweralkyoxycarbonyl group; provided that Y represents --CH₂ R⁹ only when Zis a lower alkoxycarbonyl group; that R⁴ represents a hydrogen atom R⁵is a lower alkyl group, a lower acyl group, a 2-furoyl group, a benzylgroup, a phenethyl group or a benzoyl group optionally substituted byhalogen or nitro only when Y is CH₂ R⁹ and Z is a lower alkoxy carbonylgroup; that Y can be ##STR74## and R⁴ is a lower alkyl group.
 2. Thecompound of claim 1 in which the pharmaceutically acceptable salt isselected from the group consisting of hydrochlorides, hydrobromides,bisulfites, phosphates, acidic phosphates, acetates, maleates,fumarates, succinates, lactates, tartrates, benzoates, citrates,glucanates, methanesulfonates, p-toluenesulfates, naphthalenesulfonatesand quaternary ammonium salts.
 3. A compound represented by thefollowing formula (2), or its pharmaceutically acceptable salt,##STR75## wherein A₁ represents --N═p A₂ is ##STR76## A₃ represents═CH--; R¹¹ represents a lower alkyl group; R¹² represents a phenyl groupoptionally substituted by halogen, lower alkyl or lower alkoxy, a2-furyl group, or a 2-thienyl group.
 4. The compound of claim 3 in whichthe pharmaceutically acceptable salt is selected from the groupconsisting of hydrochlorides, hydrobromides, bisulfites, phosphates,acidic phosphates, acetates, maleates, fumarates, succinates, lactates,tartrates, benzoates, citrates, glucanates, methanesulfonates,p-toluenesulfonates, naphthalenesulfonates and quaternary ammoniumsalts.
 5. A pharmaceutical composition for treatment of neurologicaldiseases induced by injury to nerve per se comprising the compound ofclaim 1 or its pharmaceutically acceptable salt as an active ingredientand a pharmaceutically acceptable carrier.
 6. A pharmaceuticalcomposition for treatment of neurological diseases induced by injury tonerves per se comprising the compound of claim 3 or its pharmaceuticallyacceptable salt as an active ingredient and a pharmaceuticallyacceptable carrier.
 7. A method for the treatment of neurologicaldiseases induced by injury to nerves per se which comprisesadministering to a patient in need thereof a pharmacologically effectiveamount of the compound of claim 1 or its pharmaceutically acceptablesalt.
 8. A method for the treatment of neurological diseases induced byinjury to nerves per se which comprises administering to a patient inneed thereof a pharmacologically effective amount of the compound ofclaim 3 or its pharmaceutically acceptable salt.
 9. A compound accordingto claim 1 having the formula ##STR77## or a pharmaceutically acceptablesalt thereof.